Category Archives: Immunology

Immunology

Human Immunology – Journal – Elsevier

Human Immunology publishes full-length, original, hypothesis-driven basic and clinical research articles as well as brief communications, reviews and editorials covering immunogenetics, transplantation immunology, autoimmunity, and immunity to infectious diseases in humans. It also publishes short population reports, which are tied to the allelefrequencies.net database, describing allele frequencies of HLA and KIR.

The journal's scope includes understanding the genetic and functional mechanisms that distinguish human individuals in their immune responses to allografts, pregnancy, infections or vaccines as well as the immune responses that lead to autoimmunity, allergy or drug hypersensitivity. It also includes examining the distribution of the genes controlling these responses in populations.

Research areas include:

Studies of the genetics, genomics, polymorphism, evolution, and population distribution of immune-related genes

Studies of the expression, structure and function of the products of immune-related genes

Immunogenetics of susceptibility to infectious and autoimmune disease, and allergy

The role of the immune-related genes in hematopoietic stem cell, solid organ, and vascularized composite allograft transplant

Histocompatibility studies including alloantibodies, epitope definition, and T cell alloreactivity

Studies of immunologic tolerance and pregnancy

T cell, B cell, NK and regulatory cell functions, particularly related to subjects within the journal's scope

Pharmacogenomics and vaccine development in the context of immune-related genes

Human Immunology considers immune-related genes to include those encoding classical and non-classical HLA, KIR, MIC, minor histocompatibility antigens (mHAg), immunoglobulins, TCR, BCR, proteins involved in antigen processing and presentation, complement, Fc receptors, chemokines and cytokines. Other immune-related genes may be considered.

Human Immunology is also interested in bioinformatics of immune-related genes and organizational topics impacting laboratory processes, organ allocation, clinical strategies, and registries related to autoimmunity and transplantation.

Original papers with new data will be given preference over uninvited reviews and meta- analyses.

As the flagship scientific publication of the American Society for Histocompatibility and Immunogenetics (ASHI), Human Immunology is primarily directed to readers with an interest in histocompatibility, immunogenetics, transplantation, anthropology/population studies, HLA disease association and pharmacogenomics. These include basic and clinical scientists as well as histocompatibility laboratory professionals.

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Human Immunology - Journal - Elsevier

Immunology

Immunology | bioRxiv

CIS checkpoint deletion enhances the fitness of cord blood derived natural killer cells transduced with a chimeric antigen receptor

Katy Rezvani, May Daher, Rafet Basar, Elif Gokdemir, Natalia Baran, Nadima Uprety, Mayela Mendt, Lucila Kerbauy, Mayra Hernandez Sanabria, Nobuhiko Imahashi, Ana Nunez, Li Li, Mohsen Fathi, Ali Rezvan, Vakul Mohanty, Pinaki Banerjee, Hila Shaim, Junjun Lu, Gonca Ozcan, Emily Ensley, Mecit Kaplan, Vandana Nandivada, Yuanxin Xi, Duncan Mak, Enli Liu, Sonny Ang, Luis Muniz-Feliciano, Jing Wang, Shahram Kordasti, Nedyalko Petrov, Navin Varadarajan, David Marin, Lorenzo Brunetti, Richard Skinner, Shangrong Lyu, Leiser Silva, Mollie Schubert, Garrett Rettig, Rolf Turk, Mark Behlke, Matthew S McNeill, Gavin Kurgan, Natalie W Fowlkes, Heng Li, Ken Chen, Marina Konopleva, Richard Champlin, Elizabeth J Shpall, Francesca Lorraine Wei Inng Lim, Yifei Shen, Mustafa Bdaiwi, Sunil Acharya, Ye Li, Xinhai Wan

bioRxiv 2020.03.29.014472; doi: https://doi.org/10.1101/2020.03.29.014472 New Results

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Immunology | bioRxiv

Immunology

Immunology | Graduate School of Biomedical Sciences

Immunology Program Guide

MERGE-INF is specifically designed to provide strong training in basic molecular and cellular immunology, the immunology of chronic diseases, as well as in-depth knowledge of the pathogenesis, diagnosis, prevention and treatment of inflammatory diseases including infections. We integrate clinical studies and patient contact throughout the training period.

The realization on the part of the scientific and medical communities that inflammation plays a role in many diseases, causing substantial morbidity and contributing to mortality, has fundamentally changed how we think about pathogenesis. Inflammation is directly involved in asthma, rheumatoid arthritis, cardiovascular disease, obesity, diabetes, osteoporosis, inflammatory bowel disease, Alzheimers disease, cancer, stroke and psychiatric disorders such as anxiety, unipolar and bipolar depression, schizophrenia, and post-traumatic stress disorder. Importantly, inflammation is involved in at least 8 of the top 10 leading causes of death in the United States today. Given the prevalence of inflammation in the human population, it is clear that research in inflammatory disease and related mechanisms should be a major scientific and medical priority.

The faculty of the Immunology Program is drawn from multiple departments, including Cellular and Molecular Immunology, Developmental, Molecular & Chemical Biology, Medicine, and Molecular Biology & Microbiology. This diversity is a distinct strength of the Program, as it assures the student broad exposure to research topics and approaches. It also maximizes opportunities for a student to find a research faculty advisor to serve as thesis mentor. Students begin the program in the summer with introductory courses and by pairing with clinical mentors that provide direct contact with patients, their diseases and their physicians. This is a critical part of developing translational research approaches to health-related research. Five or six cases are examined in detail and include a variety of diseases, such as endocarditis, systemic lupus erythematosus, hepatitis, scleroderma and asthma. An associated problem-based learning course provides interactive training in the analysis of pathogenesis.

During the first academic year students complete an Introductory course in immunology, biochemistry, advanced cellular immunology, signaling in cells of the immune system and the genetic analysis of immune responses. Beyond the first-year Introduction to Immunology and Biochemistry courses, all courses are based on primary sources and are taught as interactive tutorials. Interactive workshops in data analysis and informatics are part of the training. Training in fellowship grant writing is provided. Students are required to participate in classroom teaching for one semester.

Students complete four laboratory rotations in year one. These introduce the student to hands-on experience in a variety of techniques and research problems and familiarize them with potential thesis laboratories. Because of the flexibility designed into the program, a student may alter career objectives after admission.

The Immunology Program aims to provide a supportive environment that helps each student realize his or her fullest potential. Students are encouraged to work hard, be creative and have the confidence to be exploratory, yet at the same time to understand that science flourishes in an atmosphere of cooperation and collaboration.

We are looking for students with a curiosity-driven passion for research and the ability to perform laboratory-based experiments. The Immunology Program is dedicated to the premise that a diverse student body enriches the educational experience of all.

After a summer that introduces clinical aspect of inflammation and pathogenesis first year students become thoroughly immersed in immunology through foundation and advanced courses in the discipline. They also participate in journal club, seminars and research workshops, in addition to completing four laboratory rotations.

An unusual feature of this program is that students take their qualifying examination at the end of the first year, allowing them to concentrate on their thesis research going forward. The exam consists of a written research proposal and its oral defense. The purpose of this examination is to test the ability of the student to create and critically test hypotheses. A unique feature of our exam is that students are mentored by faculty to learn how real proposals are developed. Upon successful completion of the first year courses and the qualifying examination, students select a research mentor and begin their thesis work.

Thesis research experience is considered the core of a student's training. Students enter their labs at the beginning of year two. Typically, graduates of the Program generate at least two first author papers based on their research. Support to attend national meetings is available.

The Program has a student advisor who acts as an ombudsperson and student advocate.

The thesis research of four most recent PhD graduates illustrate the breadth of the work done by students in the Program:

Elizabeth showed how NEMO (NF-B essential modulator) functions in the T cell receptor activation pathway.

Michelle developed a genetic screen that allowed her to identify Klebsiella pneumoniae virulence factors, in particular, those that counter defense by neutrophils.

Bridget discovered that STING, a known detector of cytoplasmic DNA in macrophages and dendritic cells, is expressed in T cells and regulates their function.

Maria created a three-dimensional model of infection of the human intestine by Cryptosporidium parvum that for the first time allows long-term in vitro propagation of this protozoan parasite.

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Immunology | Graduate School of Biomedical Sciences

Immunology

Immunology/Introduction – Wikibooks, open books for an …

Immunology is the study of the organs, cells, and chemical components of the immune system. The immune system creates both innate and adaptive immune responses. The innate response exists in many lower species, all the way up the evolutionary ladder to humans, and it acts through relatively crude means against large classes of pathogens. The adaptive response is unique to vertebrates, reacting to foreign invaders with specificity and selectivity.hb

The immune system must maintain a delicate balance, with potent defensive responses capable of destroying large numbers of foreign cells and viruses while refraining from undue destruction of the host's body. When the immune system cannot mount a sufficient defense of the host, there is an immune deficiency; this is seen in HIV infection and SCID . If, on the other hand, the immune system acts too vigorously and begins to attack the host, we have autoimmunity. This is a defiance of the integral immune system property of self/nonself recognition. That is, the immune system begins attacking or forming antibodies against the host's own body tissues. Examples of autoimmune diseases include Graves' disease, Hashimoto's thyroiditis, myaesthenia gravis and type I diabetes mellitus.

The human immune system recognizes non-self entities and mounts an effector response to neutralize the organism. A faster and stronger memory response may occur upon later exposure. The memory response has been used throughout history to confer immunity upon several populations, even previous to our understanding of the physiological basis for such a response. Thucydides wrote in his History of the Peloponnesian War that persons who had been exposed to plague previously could care for the sick without danger. In the 19th century, variolation was commonplace; this was the removal of smallpox (variola virus) skin pustules which were subsequently put into small cuts in the skin of healthy people. This was itself a crude form of vaccination, with the crusty dry pustules acting as an incubator of attenuated virus. Edward Jenner would later use the cowpox virus to vaccinate (from vacca, Latin for "cow") patients against smallpox, and Louis Pasteur attenuated rabies and injected it into a small boy, naming this substance a vaccine in honor of Jenner's earlier studies in the science of immunology.

As immunology progressed, many people began to question how these vaccines worked. Why should exposure to plague in Thucycides' time confer protection only against plague and not all disease? Why should cowpox, a similar disease to smallpox but clearly a less severe virus, give milk maids sufficient immunity to resist full smallpox infection? In short, what has caused this memory response to be relatively (yet not absolutely) specific as well as selective?

First, some vocabulary:

Note: Often, antibody and immunoglobulin are used interchangeably. antigen and immunogen are used interchangeably(but to be precise, they are not the same)

There have been several competing theories of the immune response mechanism. The instructional theory of antigen interaction postulated that the antigen itself caused antibodies to fold around the antigen in a certain way; this theory was later disproven. The selection theory states that the body creates many different sidechains on antibodies, and the antigen "selects" the correct antibody; in other words, the body creates every possible permutation of chemical sidechain-specific antibodies, and when an antigen enters the body, it is matched up with antibodies that correspond to its epitopes. The current theory of immune response is known as the clonal selection theory, which states that an individual lymphocyte (specifically, a B cell) expresses receptors specific to the distinct antigen, determined before the antibody ever encounters the antigen. Binding of Ag to a cell activates the cell, causing a proliferation of clone daughter cells.

Innate immunity is basic and nonspecific. It includes:

antigen-presenting cells (APCs))

Certain cells "eat up" foreign invaders; this is termed phagocytosis. Many of these cells are known as Antigen-Presenting Cells (APCs) because they break apart the ingested pathogen and display certain epitopes of the antigen on their surface. In this way, they localize the presentation of antigen, forming a vital link between the innate response and the adaptive response. Lymphocytes (such as B cells and T-helper cells) will have antigen presented to them, initiating the adaptive response. Monocyte-derived cells are common APCs, and they include tissue macrophages and monocytes within the blood; eutrophils are also APCs. APCs are discussed further below, in the section on cells of the immune system.

The skin contains epidermis and dermis. The epidermis contains tightly packed epithelial (cytokeratin positive) cells with keratin waterproofing. The dermis contains connective tissue blood vessels hair follicles, sweat glands, and sebaceous glands. Sebaceous glands secrete sebum; this contains fatty acids and lactic acid, lowering skin pH to 35.

Mucous membranes contain normal flora, mucus, and cilia. Mucous membranes are found in the nose, eyes, mouth, urogenital, and anal regions of the body. Flora refers to bacteria that inhabit the human body in a relative steady-state; the gastro-intestinal tract contains a large number of these bacteria, and different areas of the world contain different flora. It is for this reason that people contract Traveler's Diarrhea; in short, flora from one region of the world are more dangerous because the body has not acclimated to their presence. Mucus contains certain mucin proteins, inorganic salts, and water; it is secreted from goblet cells. Cilia acts to sway back and forth during two phases, known as the power stroke and the recovery stroke; this allows mucus to be swept out of the body, either proximodistally from the lungs up the respiratory tract, or down the GI tract through the intestines, culminating in defecation. The enteric nervous system causes contractions of the gut, moving foodstuffs, waste, and bacteria/toxins down the digestive tract. This is just one example of disparate systems of the body working together with the immune system proper. Other examples are skeletal muscles, which squeeze blood along the veins and lymph along the lymph vessels, or the nervous system, which supports a rise in body temperature in response to infection.

Some bacteria can attach to mucous membranes via fimbriae or pili, which attach to special glyoproteins/glycolipids on the epithelial cells of mucous membranes.

Several antimicrobial compounds mediate the innate response.

peptidoglycan in bacterial cell walls

cells (it is a paracrine factor), inducing a generalized antiviral state

pathogen cell membranes

their lipid membranes or agglutinating them

via pattern recognition to certain classes of molecules; TLR4, for example, recognizes lipopolysaccharide (LPS) on gram-negative bacteria

Classical biology puts several characteristics together as an inflammatory response. These included redness (erythema, rubor), heat (calor), swelling (edema, tumor), pain (dolor), and loss of function (functio laesa). The physiological processes that bring about these symptoms are central to the innate immune response.

Erythema results from constriction of post-capillary venules in tissue beds and vasodilation in pre-capillary arterioles/metarterioles. This results in an increase of hydrostatic pressure in the capillary bed, overcoming the osmotic pressure of the interstitial fluid and causing exudate (high-protein fluid with acute-phase proteins like C-reactive protein and macrophages) to flow into the interstitial tissue. This flowing of exudate also allows the factors of the clotting cascade to enter areas of tissue damage, forming clots and, eventually, scars. Certain inflammatory factors also cause phagocytic cells to enter the damaged tissue. The now-permeable capillaries are traversed by these phagocytes in response to chemotaxis, the release of factors that lure the cells to the site of injury. The cells first approach the side of a capillary (margination), move through the spaces between capillary endothelial cells (diapedesis), and then enter the tissue itself. Histamine helps to mediate this response, and certain factors (such as bradykinin and possibly prostaglandins) stimulate skin pain receptors. Thus, blood flows into the tissue, causing redness, warmer steady-state temperature, swelling, and pain; loss of function is a secondary effect of these four states.

Adaptive immunity occurs in response to antigen exposure. It is specific, and it shows memory. As long as an antigen is made of the normal chemical elements we experience in biological systems (e.g. Carbon, Nitrogen, Sulfur, Hydrogen, Oxygen), we can form an adaptive response to it. This is how we fight off new diseases, and it has even been shown that we can create antigens in the laboratory that have never before existed on Earth, only to have animals mount competent immune reactions to them. As stated earlier, the adaptive immune system's specificity is tempered with an ability to differentiate between self and non-self antigen; simply put, the body doesn't attack its own cells, unless they have been invaded by virus and ask to be sacrificed for the sake of the host. When the immune system does attack the body, this is a disease state: autoimmunity.

The primary response takes 56 days, but the memory (secondary) response will be swifter and deadlier. It includes:

Blood cells are made in the bone marrow of adults. Leukocytes are white blood cells (WBCs). This includes monocytes (which become myriad cell types in the body, most importantly macrophages), granulocytes (neutrophils, basophils, eosinophils), and lymphocytes. Of all the leukocytes, the lymphocyte class are the most preeminent in the adaptive immune response. On a peripheral blood smear, lymphocytes are approximately the size of erythrocytes (red blood cells, RBCs), although they can be larger if activated and have a characteristic "clock-face" nucleus if they are B cells. Lymphocytes are so named because fewer than 1% are present in the circulating blood; the rest lie in the lymph nodes, spleen and other lymphoid organs. T lymphocytes leave the bone marrow, travelling to the thymus gland, where they mature and gain their specificity for the diverse antigens the body might come into contact with; additionally, any T cells that react against the body's own epitopes are selected against (killed) in the thymus, in an effort to stop any possible autoimmunity. A similar process occurs in the bone marrow in the case of B lymphocytes. B cells are conveniently named ("B for bone marrow"), but this is just a coincidence; it turns out that they are named B cells after the Bursa of Fabricius, a small pouch in the cloaca (lower large intestine, cloaca Latin for "sewer") of birds.

B cells leave the bone marrow with their specific membrane bound Ig (antibody) already specified. The Ig itself is made up of two medial heavy chains (both identical) with two lateral light chains (also identical) attached to the "top" of the heavy chains, which form a Y shape. Before they encounter antigen, B cells are known as "naive." Once they encounter antigen, the naive B cells will undergo clonal expansion; an activated B cell will form some daughter memory B cells and some plasma cells. The memory cells will lie in wait for a second encounter with the antigen, while the plasma cells will begin a massive secretion of antibody (Ig). B cells can bind to antigen when it is free and unprocessed in the body, much like APCs can.

Before moving on to T lymphocytes, it should be noted that certain cell surface molecules distinguish each person's unique immune system profile. The Major Histocompatibility Complex (MHC, or HLA) is a type of protein expressed on the surface of host cells that interacts with T-cell receptors (TCRs) of T cells. Virtually all the body's cells, including APCs, express class I MHC (MHC-I) on their surface. Only APCs express class II MHC (MHC-II). Thus, most body cells express MHC-I, while APCs express both MHC-I and MHC-II. When antigen enters a body cell and is broken down, the products of this breakdown are sent to the surface of the cell coupled with MHC-I. This forms the MHC-I/Ag complex, and usually occurs when a virus or bacterium enter a cell and are broken down by intracellular defenses. This can also occur in APCs, but APCs additionally process the antigen that they phagocytose, presenting it as an MHC-II/Ag complex on the surface of their cells.

T cells can be subdivided into two broad types: T helper cells and T cytotoxic cells. T helper cells express a T-Cell Receptor (TCR) that will interact with APC surfaces. Specifically, they interact with the MHC-II/Ag complex on the surface of APCs, and the TCR is stabilized in its binding by a CD4 receptor. CD stands for "cluster of differentiation," and is simply a class of cell receptor which occurs predominantly on T cells. T helper cells contain CD4 receptors and T cytotoxic cells contain CD8 receptors. Upon binding, T helper cells release cytokines, which act as chemotactic agents to call for more T helper cells, T cytotoxic cells, APCs, and B cells.

T cytotoxic cells encounter body cells that have been invaded and are presenting MHC-I/Ag on their surface. Tc cells extend their TCR to the MHC-I/Ag complex and stabilize this interaction with their CD8 receptor arms. Upon binding, the CD8+ cells differentiate, much like naive B cells, into memory T cells and cytotoxic T lymphocytes (CTLs), effector cells that cause the MHC-I/Ag-presenting cell (the "altered self cell") to die (apoptose). CTLs trigger apoptosis by secreting a perforin that allows the entry of a serine protease (Granzyme B) which activates intracellular executioner caspases. It should be noted that cancer cells can also become altered self cells, and CTLs are very important in the destruction of cancerous cells. T cells can interact with antigen only after it has been processed, either by a normal body cell (MHC-I) or by an APC (MHC-II).

Difference between the two types of T cells:

presented on MHC-II, via binding with TCR and CD4.

proteins), broken down by lysosomes in many types of body cells, presented on MHC-I, via binding with TCR and CD8.

Note that it is both the antigen and the MHC that is presented to T cells; each person has a unique MHC. This is why we must type for bone marrow transplantswe don't want people producing tons of new immune cells in bone marrow that think every MHC in the body is actually just antigen; when this does occur, it is called graft-vs.-host disease. Not only would the new bone marrow make cells that attacked every body cell's MHC, but when the body did present Ag on MHC, the lymphocytes from the transplant would not be able to recognize this MHC-I/Ag complex (although the MHC-II complex cells would be made in the new bone marrow, and thus APCs could, in some cases, still present). Unfortunately, these APCs would be very busy presenting the host's own body cells; clearly MHC typing (also known as HLA typing) for bone marrow transplants is a necessary result of the elegant self-nonself recognition of the human immune system. It is also worth noting that we are only as good as our presenting molecules. Some people have MHC genes that are not as good at presenting antigen, and thus some people have more vigorous immune respones than others.

The cellular and humoral responses of the adaptive immune system are linked via the T helper cell-B cell interaction. The T helper cell secretes cytokine factors to encourage chemotaxis of B cells to the site of infection as well as B cell differentiation and growth. B cells themselves, in their effector plasma B cell form, release antibodies into the blood.Antigens, or foreign substances that enter the body,are very harmful to the Immune System. But when specific antibodies are produced to bind with an antigen, the foreign substance becomes harmless and is delivered to the lymph. Antibodies are also very important in the complement system; this is an example of the vertebral adaptive immune response making good use of the relatively primitive innate immune response. Antibodies to the body's own cells are a very real danger. Type I diabetes may be caused by an autoimmune response, where the body makes antibodies to its own Beta cells in the pancreatic Islets of Langerhans. Graves' disease is a condition where the body produces antibodies to receptors in the follicular cells of the thyroid; these Ab keep the cells constantly activated, giving the patient hyperthyroidism and increasing their metabolism, to adverse effect. The interesting counterpoint to this is Hashimoto's thyroiditis; here the body makes antibodies to thyroid follicular cells' receptors, but in this case the cells are shut down by the Ab, and the patient endures hypothyroidism.

Autoimmunity due to antibody overreaction (hypersensitivity) is a huge problem, and it is a much greater problem in women than in men. Women tend to have a higher titer of immunoglobulin (antibody), and thus they exert a stronger (and sometimes overwhelming) immune response. For example, for every one man who gets Graves' disease, 8 women will contract it.

Antibodies are often given to produce a short-lived humoral immunity in emergency situations. Many antivenoms are actually horse immunoglobulin, produced in order to bind the venom until it can be cleared from the body.

It should be noted that all of the above-mentioned immune responses result in the destruction or agglutination of foreign pathogen. The goal of the immune response is three-fold:

The immune responses listed above show the intimate interaction between the innate and adaptive immune systems, as well as the subclasses of adaptive responses. The clonal selection theory of immune response, introduced above, is clear in the action of lymphocytes. Clonal selection simply means that antigen is presented to many circulating naive B and (via MHC) T cells, and the lymphocytes that match the antigen are "selected" to form clones of themselves, both memory and effector. This mass production of daughter cells is termed clonal expansion, and it is essential in the understanding of the theoretical basis of immunology. Not only this; clonal selection is used negatively in the lymphoid organs. Here, the body's own epitopes are presented to the infant lymphocytes; those that react are recognized as traitors and destroyed before they (and their future cloned daughters) can leave and wreak havoc in the body.

Back to Immunology || Next Chapter: Organs of the Immune System

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Immunology

Immunology Research Areas: R&D Systems

Bio-Techne appreciates the critical role that you and our products and services play in research efforts to further scientific innovation and discovery. We are continually assessing our manufacturing and supplier capabilities during the COVID-19 situation and are implementing precautionary measures to ensure uninterrupted supply of products and services. Currently, and as we abide by local shelter in place orders across the world, we are fully operational and do not anticipate any material supply disruptions across our Bio-Techne brands and product lines. As the situation evolves, our goal is to utilize preventive measures to reduce the threat that COVID-19 poses to our ability to meet the needs of our customers globally.

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Immunology Research Areas: R&D Systems

Immunology

Lilly and Sitryx Announce Licensing and Research Collaboration to Discover and Develop New Immunometabolic Medicines – Yahoo Finance

INDIANAPOLIS and OXFORD, England, March 31, 2020 /PRNewswire/ --Eli Lilly and Company (NYSE: LLY) today announced an exclusive global licensing and research collaboration with Sitryx, a biopharmaceutical company focused on regulating cell metabolism to develop disease-modifying therapeutics in immuno-oncology and immuno-inflammation. The collaboration will study up to four novel preclinical targets identified by Sitryx that could lead to potential new medicines for autoimmune diseases.

"As Lilly seeks to develop new and unique medicines for people suffering with autoimmune diseases, we are actively exploring a variety of scientific approaches both in our own labs and with external partners," said Ajay Nirula, M.D., Ph.D., vice president of immunology at Lilly. "Regulating the metabolism of immune cells is a promising approach to treating these diseases, and we look forward to working with the talented researchers at Sitryx to advance their novel immunometabolism targets."

"We are excited to partner with Lilly, one of the global leaders in the field of immunology, to pursue the discovery of novel targets and the development of innovative therapies for autoimmune and inflammatory diseases in the fast-emerging area of immunometabolism," said Neil Weir, Ph.D.,chief executive officer of Sitryx. "This agreement is transformational for Sitryx and further validates the strength of our scientific expertise and that of our Founder network and the potential for Sitryx to become a leader in this field."

Under the terms of the agreement, Sitryx will receive an upfront payment of $50 million and Lilly will make a $10 million equity investment in Sitryx. Sitryx will be eligible to receive potential development milestones up to $820 million, as well as commercialization milestones and royalty payments on potential sales in the mid- to high-single digit range. In return, Sitryx will grant Lilly an exclusive, worldwide license to develop and commercialize up to four novel immunometabolism targeted therapeutics, including Sitryx's two lead projects. Lilly and Sitryx will establish a 5-year research collaboration to support the development of the therapeutics, with Sitryx responsible for drug discovery, while Lilly will fund and manage the clinical development and commercial phase of the collaboration.

This transaction is subject to customary closing conditions. The transaction will be reflected in Lilly's reported results and financial guidance according to Generally Accepted Accounting Principles (GAAP). There will be no change to Lilly's 2020 non-GAAP earnings per share guidance as a result of this transaction.

About SitryxSitryx is a biopharmaceutical company focused on regulating cell metabolism to develop disease-modifying therapeutics in immuno-oncology and immuno-inflammation. Sitryx's proprietary science is led by a highly experienced management team and supported by world class academic founders. Sitryx was founded by six world-leading researchers in the field of immunology and metabolism; Houman Ashrafian, Luke O'Neill, Jonathan Powell, Jeff Rathmell, Michael Rosenblum and Paul Peter Tak. Together they have published more than 1,000 papers in the field, making multiple key breakthroughs in our understanding of how critical energetic status is to the behavior of immune cells and in the broader field of immunology. In 2018, Sitryx raised $30 million Series A funding from an international syndicate of specialist investors including SV Health Investors, Sofinnova Partners, Longwood Fund and GSK. The company has a pipeline of projects at multiple stages of drug discovery. Sitryx is headquartered in Oxford, UK. For more information, please visit http://www.sitryx.com.

AboutEli Lilly and CompanyLilly is a global healthcare leader that unites caring with discovery to create medicines that make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us atwww.lilly.com. C-LLY

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Lilly Forward-Looking StatementThis press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about the benefits of a collaboration between Lilly and Sitryx, and reflects Lilly's current beliefs. However, as with any such undertaking, there are substantial risks and uncertainties in the process of drug development and commercialization. Among other things, there can be no guarantee that Lilly will realize the expected benefits of the collaboration, or that the collaboration will yield commercially successful products. For a further discussion of these and other risks and uncertainties that could cause actual results to differ from Lilly's expectations, please see Lilly's most recent Forms 10-K and 10-Q filed with the U.S. Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.

Refer to:

Mark Taylor; mark.taylor@lilly.com; (317) 276-5795 (Lilly Media)

Kevin Hern; hern_kevin_r@lilly.com; (317) 277-1838 (Lilly Investors)

Consilium Strategic Communications; +44 (0)20 3709 5700 (Sitryx)

Eli Lilly and Company logo. (PRNewsfoto/Eli Lilly and Company)

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Immunology

RAPT Therapeutics Reports Fourth Quarter 2019 Financial Results and Provides Business UpdateCompany bolsters cash by $116 million with public…

SOUTH SAN FRANCISCO, Calif., March 30, 2020 (GLOBE NEWSWIRE) -- RAPT Therapeutics, Inc.(Nasdaq: RAPT), a clinical-stage, immunology-based biopharmaceutical companyfocused on discovering, developing and commercializing oral small molecule therapies for patients with significant unmet needs in oncology and inflammatory diseases, today reported financial results for the fourth quarter ended December 31, 2019 and provided an update on recent operational and business progress.

2019 was an especially productive year for RAPT with the completion of our initial public offering and the generation of encouraging early clinical data for our two lead immunology-based programs: FLX475 for the treatment of multiple cancers and RPT193 for the treatment of atopic dermatitis and other allergic inflammatory diseases, said Brian Wong, M.D., Ph.D., President and CEO of RAPT Therapeutics. In addition, we partnered with Hanmi for FLX475 in Asia, a region with a high prevalence of charged tumors, and we strengthened our balance sheet substantially with our follow-on offering in February 2020.

Dr. Wong continued, For our ongoing Phase 1/2 study of FLX475, we continue to enroll and treat patients with multiple types of advanced cancer, though we are monitoring the impact of COVID-19 on our clinical trial sites both within and outside of the U.S. Because of the life-threatening nature of the cancers, we are working site by site to ensure that patients receive treatment and follow up as close to protocol-specified intervals as feasible. Our primary objective is patient safety and we will adapt to local circumstances as needed.

For RPT193, we successfully completed the healthy volunteer portion of the study. We have made the decision to pause the enrollment of patients with atopic dermatitis in the Phase1b portion of our clinical study for RPT193 in an effort to support clinicians and healthcare facilities that are prioritizing the fight against COVID-19, while safeguarding the health and safety of patients and clinicians who would be involved in our trial. We intend to resume enrollment as soon as practical once we expect patients can be treated and followed up consistently under safer public health conditions.

Financial Results for the Fourth Quarter and Full Year Ended December 31, 2019

Fourth Quarter Ended December 31, 2019Net loss for the fourth quarter of 2019 was $13.2 million, compared to $9.4 million for the fourth quarter of 2018.

Research and development expenses for the fourth quarter of 2019 were $10.2 million, compared to $8.4 million for the same period in 2018. The increase was primarily due to clinical costs related to the advancement of RPT193 and FLX475 as well as the personnel costs associated with these studies offset by outsourced research and development and lab supplies.

General and administrative expenses for the fourth quarter of 2019 were $2.6 million, compared to $1.3 million for the same period in 2018. The increase was due to an increase in consulting costs as well as accounting and audit-related costs as well as other expenses associated with being a public company.

Full Year Ended December 31, 2019Net loss for the year ended December 31, 2019 was $43.0 million, compared to $36.1 million for the same period in 2018.

Research and development expenses for the year ended December 31, 2019 were $34.9 million, compared to $31.8 million for the same period in 2018. The increase was primarily due to increases in costs relating to the clinical development of RPT193 and FLX475, facilities and personnel, offset by decreases in costs relating to lab supplies and outsourced research and development.

General and administrative expenses for the year ended December 31, 2019 were $8.7 million, compared to $5.2 million for the same period in 2018. The increase was primarily due to increases in professional service fees related to preparations for our initial public offering.

As of December 31, 2019, we had cash and cash equivalents of $77.4 million. In February 2020, we received net proceeds of approximately $69.7 million resulting from our follow-on public offering of 2,500,000 shares of common stock.

AboutRAPT Therapeutics, Inc.RAPT Therapeutics is a clinical stage immunology-based biopharmaceutical company focused on discovering, developing and commercializing oral small molecule therapies for patients with significant unmet needs in oncology and inflammatory diseases. Utilizing its proprietary discovery and development engine, the Company is developing highly selective small molecules designed to modulate the critical immune drivers underlying these diseases. RAPT has discovered and advanced two unique drug candidates, FLX475 and RPT193, each targeting C-C motif chemokine receptor 4 (CCR4), for the treatment of cancer and inflammation, respectively. The Company is also pursuing a range of targets, including general control nonderepressible 2 (GCN2) and hematopoietic progenitor kinase 1 (HPK1), that are in the discovery stage of development.

Forward-Looking StatementsThis press release contains forward-looking statements. These statements relate to future events and involve known and unknown risks, uncertainties and other factors that may cause our actual results, performance or achievements to be materially different from any future performances or achievements expressed or implied by the forward-looking statements. Each of these statements is based only on current information, assumptions and expectations that are inherently subject to change and involve a number of risks and uncertainties. Forward-looking statements include, but are not limited to, statements about the impact of COVID-19 on the clinical development of FLX475 and RPT193 and the anticipated timing of clinical data. Detailed information regarding risk factors that may cause actual results to differ materially from the results expressed or implied by statements in this press release may be found in RAPTs Form 10-K expected to be filed with the Securities and Exchange Commission on or about March 30, 2020 and subsequent filings made by RAPT with the Securities and Exchange Commission. These forward-looking statements speak only as of the date hereof. RAPT disclaims any obligation to update these forward-looking statements.

RAPT Media Contact:Angela Bittingmedia@rapt.com(925) 202-6211

RAPT Investor Contact:Sylvia Wheelerswheeler@wheelhouselsa.com

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RAPT Therapeutics Reports Fourth Quarter 2019 Financial Results and Provides Business UpdateCompany bolsters cash by $116 million with public...

Immunology

Mastercard-sponsored therapeutics accelerator awards $20 million gr… – Finextra

Today, the partners in the COVID-19 Therapeutics Accelerator announced grants of $20 million to three institutionsthe University of Washington, University of Oxford, and La Jolla Institute for Immunologyto fund clinical trials in order to identify highly potent immunotherapies for the COVID-19 pandemic.

These grants to leading institutions in their fields will advance our understanding of how existing drugs and antibodies can contribute to addressing the pandemic were facing around the world, said Mark Suzman, chief executive officer of the Bill & Melinda Gates Foundation. These initial investments through the COVID-19 Therapeutics Accelerator will bring rigor to the study of these potential solutions. The way forward will be informed by sound science and shared data.

In addition, newly announced funding from government and philanthropic donors has added to the Accelerators initial funding. The Chan Zuckerberg Initiative committed $25 million and the U.K. government committed 40 million last week. The additional funds will allow the Accelerator to continue making grants to study repurposed drugs and investigate biological compounds for activity against COVID-19. More funding is needed to move promising therapies through development and scale-up.

Studying repurposed drugs to prevent infection

Two of the newly announced trials will fund an investigation of two well-established drugs, hydroxychloroquine and chloroquine, that have known antiviral properties. These drugs have been used to treat malaria and a variety of rheumatological conditions for more than 50 years. The trials aim to determine whether the drugs are effective as pre- and post-exposure preventive therapy for COVID-19. While these drugs both show initial promise, rigorous scientific evidence is needed to make decisions on how, where and within which populations to use them in this pandemic.

The University of Washington will conduct a multi-site clinical trial in Western Washington and the New York City area, in collaboration with New York Universitys School of Medicine, investigating whether hydroxychloroquine can effectively prevent COVID-19 in people already exposed to the infection. The trial will enroll up to 2,000 asymptomatic men and women who are close contacts of persons with confirmed or pending COVID-19 diagnoses. Participants will be randomly assigned to take hydroxychloroquine or a placebo over two weeks, and samples will be collected and tested daily to confirm new COVID-19 infections across the two groups. Sandoz, a Novartis division, has donated the hydroxychloroquine doses needed to conduct the study. Participant enrollment will begin in April, and results will be available in late 2020.

The Mahidol Oxford Tropical Medicine Research Unit (MORU) will lead a placebo-controlled prophylaxis study of chloroquine and hydroxychloroquine in preventing COVID-19 in at-risk health care workers, frontline staff, and other high-risk groups. At least 40,000 participants in Asia and Europe will be randomized to receive either chloroquine (East Asian countries), hydroxychloroquine (United Kingdom and Europe), or a matched film-coated placebo as daily prophylaxis for three months. The one-year project, known as COPCOV, aims to determine definitively whether these drugs can prevent COVID-19 and thus protect the vital health care workforce. Participant enrollment will begin in April and initial results will be available by the end of the year.

Nick Cammack, COVID-19 Therapeutics Accelerator Lead at Wellcome, said: Investment in research is the worlds only exit strategy from COVID-19. Drugs, vaccines, and diagnostics are vital to saving lives, to ending this pandemic, and to preventing it from happening again. Now is the time to evaluate whether existing drugs will prove to be safe and effective. We urge others to join us in this collective global effort. Investing now, at scale, in the COVID-19 Therapeutics Accelerator is vital if we are to change the course of this pandemic.

Advancing immunological therapies

In addition to funding drug trials, the Accelerator will provide $1.73 million to the La Jolla Institute for Immunology to establish a Coronavirus Immunotherapy Consortium, known as CoVIC. The effort will bring together scientists from around the world and enable them to share and evaluate candidate antibodies side by side in a blinded, multidisciplinary analysis to identify ideal therapeutic combinations. Antibody therapies can be used to protect frontline health care workers, contacts, and others who are exposed, as well as treat those who have already become sick.

Todays grants are an important next step in the Therapeutic Accelerators commitment to identifying and scaling treatments to combat COVID-19, said Mike Froman, vice chairman of Mastercard. In order to provide therapeutic solutions to this global pandemic, particularly for those most vulnerable, we need to speed up the research and development process through a collaborative funding effort by the private sector, philanthropic organizations, and governments. We welcome the participation of additional organizations that can contribute the resources needed to help bring an end to this crisis.

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Mastercard-sponsored therapeutics accelerator awards $20 million gr... - Finextra

Immunology

Collaboration initiated to develop COVID-19 immunotherapy – Drug Target Review

The University of Georgia and CEL-SCI Corporation have partnered to develop an immunotherapy to combat the COVID-19 coronavirus using the Ligand Antigen Epitope Presentation System (LEAPS) technology.

A collaboration between the University of Georgias (UGAs) Center for Vaccines and Immunology, US, and CEL-SCI Corporation has been formed to develop a Ligand Antigen Epitope Presentation System (LEAPS) COVID-19 immunotherapy. The immunotherapy candidate aims to treat patients at highest risk of dying from the novel coronavirus.

According to the new partners, the work will commence with pre-clinical studies based on experiments previously conducted with the LEAPS immunotherapy platform in collaboration with the US National Institutes for Allergies and Infectious Diseases (NIAID) against another respiratory virus, influenza A (H1N1). Those successful studies demonstrated that LEAPS peptides, given after virus infection has occurred, reduced morbidity and mortality in mice infected with H1N1.

It is suggested, based on studies with H1N1, that a LEAPS coronavirus SARS-CoV-2 immunotherapy may reduce or prevent the progression of the viral infection and prevent tissue damage from inflammation resulting from lung infiltration by the virus. By stimulating the correct immune responses without producing unwanted inflammatory responses associated with lung tissue damage, LEAPS immunotherapy may be particularly beneficial in those patients who are at highest risk of dying from COVID-19.

a LEAPS coronavirus SARS-CoV-2 immunotherapy may reduce or prevent the progression of the virus infection

The studies will utilise the LEAPS peptide approach that elicits both a cell-mediated antiviral response and an anti-inflammatory immunomodulating response by activating CD8 T lymphocytes. Previous studies showed that LEAPS immunogens can prevent lethal infection by herpes simplex virus (HSV) and H1N1 and stop the inflammatory disease progression of rheumatoid arthritis in animal models. LEAPS peptides against HSV demonstrated that the T-cell response was sufficient to prevent viral disease and if there was residual virus production, anti-viral antibodies were generated to further control the spread of the virus.

The proposed LEAPS peptides for the COVID-19 study are directed towards antigens within the NP protein of SARS-Cov-2 virus that elicit cytolytic T-cell responses. Unlike the viral glycoprotein Spike antigens, which are important for antibody-based vaccines, these NP-antigens are less variable between viral strains and less likely to change in response to antibodies elicited by prior infection or other vaccines. Cytolytic T-cell responses attack the virus infected cellular factories within the infected host in order to eliminate the source of virus and help subdue the infection.

We are eager to commence these studies, which if successful, may lead to clinical trials in humans to address the immediate and critical need to treat COVID-19 in the most vulnerable patients. We are very pleased and honoured to partner with Dr Ted Ross and his team and the UGA Center for Vaccines and Immunology. Their world-renowned expertise and world-class facilities will accelerate the development of LEAPS COVID-19 immunotherapy, stated CEL-SCI Chief Executive Officer Geert Kersten.

Dr Ross commented: LEAPS has the potential to be a powerful tool against SARS-CoV-2, the causative agent of COVID-19, based on its dual anti-viral and anti-inflammatory properties. Combining the prior pre-clinical data of LEAPS against H1N1 with our advancing knowledge of COVID-19, we aim to rapidly evaluate this technologys potential to meet the urgent need to treat patients at greatest risk of dying from this global pandemic. UGSs biocontainment labs at the Center for Vaccines and Immunology are ideally suited for these studies and will serve as critical assets in this collaboration with CEL-SCI.

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Collaboration initiated to develop COVID-19 immunotherapy - Drug Target Review

Immunology

Zoonotic diseases: Why are infections from animals so dangerous to hu – Medical News Today

In the wake of the COVID-19 global pandemic, which started when the virus SARS-CoV-2 jumped from animals into humans, we ask an important question why are infections acquired from animals so dangerous to human health?

While it is not yet clear which animals were the source of the new coronavirus was it bats? Was it pangolins? Was it both? scientists are sure that SARS-CoV-2, the virus that causes COVID-19, originated from animals.

The numbers of confirmed COVID-19 cases across the world are staggering. According to Johns Hopkins University, more than 730,000 people have contracted the virus and 34,000 people have died.

But zoonotic diseases that is, diseases acquired from animals were affecting vast numbers of people across the world before COVID-19 took center stage.

Stay informed with live updates on the current COVID-19 outbreak and visit our coronavirus hub for more advice on prevention and treatment.

An international report from 2012, for example, informed that a total of 56 such diseases were responsible for 2.5 billion cases of illness and 2.7 million deaths across the globe each year. These illnesses included rabies, toxoplasmosis, Q fever, Dengue fever, avian influenza, Ebola, and anthrax.

Furthermore, respiratory, flu-like diseases acquired from animals wreaked havoc in the past century. The Spanish flu caused 50 million deaths in 1918, and the Hong Kong flu caused 700,000 deaths in 1968.

So, why are diseases that humans acquire from animals so dangerous? Part of it is due to our immune system. Part of it is natural selection. The specific animal that transmits the virus may also play a role.

Below, we explore some of these factors and how they intertwine.

One reason viruses from animals are so dangerous to humans is that people have no means to deal with them. Our immune system was never introduced to these novel viruses, so it doesnt know how to respond to the uninvited guest.

Researchers explain that most of the viruses that enter the human body are successfully destroyed by the immune system or pass through our gastrointestinal system. However, now and then, an animal virus manages to replicate within a human host.

The moment where the animal virus replicates within the body of the first human is crucial. At this critical point, the virus can mutate and evolve under the selective constraints of the human body for the first time, adapting and improving itself for replication in this new host.

As this occurs, the human immune system must retaliate. It needs to catch up with the virus evolution and create an immune response. The human body has never been confronted with this threat before, and therefore, has no pre-existing immunity in its arsenal so it must devise one fast.

But, this defense part of the adaptive immune system takes days or longer to activate. In the meantime, the virus may have already evolved to replicate faster or even escape the immune systems retaliation.

In other words, the animal virus and the human immune system have entered an arms race and like with any arms race, one of the two competitors could win, or both competitors could reach a stalemate.

Medical News Today spoke to Christopher Coleman, assistant professor of Infection Immunology at the University of Nottingham in the United Kingdom, about animal viruses, human hosts, and the role of evolution and natural selection.

[T]he general assumption, he explained, is that as viruses evolve to a host, they become less dangerous to that host (they want to ensure their own transmission so dont want to rapidly kill the host before they get a chance [to replicate]).

This is by no means [always] true, but a virus that adapts to humans might be less dangerous in the long term because the evolutionary arms race between virus and host has reached a sort of stalemate where neither is perfectly happy, but neither is killed off.

Christopher Coleman

Furthermore, a virus that fully adapts to an animal host may be completely harmless to humans, Coleman continued.

The scientist whose main research focuses on highly pathogenic human coronaviruses gave examples of aggressive animal viruses within the coronavirus family. These include the infectious bronchitis virus of chickens, feline infectious peritonitis virus in cats, or transmissible gastroenteritis virus, which is near 100% fatal in piglets.

None of these [viruses] are known to infect or cause any disease in humans, Coleman said.

On the other hand, a virus that evolves in animals but also has an ability to infect humans may be more deadly if and or when it infects humans.

This may be especially true when the animals immune systems are very different from those of humans, or when the animals have special defense mechanisms that humans lack.

For instance, the fact that very harmful viruses such as SARS, MERS, and Ebola have all originated in bats begs the question what do bats have that we dont?

How can bats fly around carrying viruses that, in some cases, are extremely deadly to humans (such as Ebola), but that do not seem to harm these creatures in the slightest?

A new study, led by Cara Brook, a postdoctoral Miller Fellow at the University of California Berkeley, asked this very question. The research shows how bats unique immune capabilities enable them to carry and maintain a high viral load without getting sick themselves.

[S]ome bats, explain Brook and colleagues in their paper, have an antiviral immune response called the interferon pathway perpetually switched on.

In most other mammals, having such a hyper-vigilant immune response would cause harmful inflammation. Bats, however, have adapted anti-inflammatory traits that protect them from such harm.

Cara Brook et al

This is all great news for bats, but what does it do for other mammals? Sadly, not much. The fact that bats have such good defenses means that the virus has all the encouragement it needs to replicate more quickly.

The bats unique immune capabilities eventually make the viruses stronger. It is like training with an outstanding competitor and getting stronger as a result.

Brook and her team carried out experiments using cell lines from two species of bats. The results showed that in both bat species, the strongest antiviral responses were countered by the virus spreading more quickly from cell to cell.

This suggests that bat immune defenses may drive the evolution of faster transmitting viruses, and while bats are well protected from the harmful effects of their own prolific viruses, other creatures, including humans, are not.

Cara Brook et al.

Our immune system would generate widespread inflammation if attempting this same antiviral strategy. But bats appear uniquely suited to avoiding the threat of immunopathology, says Brook.

In the case of the new coronavirus, multiple theories are circulating about the specific animal that passed on SARS-CoV-2 to humans. Scientists have implicated pangolins or even snakes as possible carriers.

Pinning down specific mammals is vital because the animal can offer insights into the genetic structure of the virus and ways to tackle it. However, it is essential not to discount the possibility that the new coronavirus might have several animal sources.

Commenting on the theory that humans contracted SARS-CoV-2 from pangolins, Coleman said: Its as good a theory as any [] This, of course, does not mean that pangolins are the only source it may be that there are other species.

For example, with the original SARS-CoV, civet cats were the most famous species involved, but there were other small mammals infected. Also, although dromedary camels are the source of MERS-CoV, there is strong evidence that other camelids can also be infected.

Regardless of which animals specifically gave humans the new coronavirus, it may be more important to ask, when and where did the virus mutate?

In a recent study, researchers led by Kristian Andersen, Ph.D., an associate professor of immunology and microbiology at the Scripps Research Institute in LaJolla, CA, used the available genomic data to determine whether the origin of the new coronavirus was natural or made by humans.

Having determined that the virus is the result of natural evolution, the authors explain that depending on whether the virus adapted in its current form in animals or humans, the course of the new coronavirus pandemic could be quite different.

[I]f SARS-CoV-2 pre-adapted in another animal species, write the authors in the journal Nature, then there is the risk of future re-emergence events.

In other words, if the virus evolved to its current state in animals, then animals would continue to pass it amongst each other, and the virus could jump back into humans at any point.

Furthermore, the researchers suggest that this scenario would explain why the virus spread so quickly. Seeing that it had already developed its pathogenic traits in animals, SARS-CoV-2 was already trained to spread and replicate quickly once it entered its first human host.

In contrast, write Andersen and colleagues, if the adaptive process occurred in humans, then even if repeated [animal-to-human] transfers occur, they are unlikely to take off without the same series of mutations, therefore minimizing the chances of another outbreak.

For now, it is impossible to know which of the two scenarios is more likely. Only time, and more research, will tell.

For live updates on the latest developments regarding the novel coronavirus and COVID-19, click here.

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Zoonotic diseases: Why are infections from animals so dangerous to hu - Medical News Today