Immunology Lecture 28 Study Guide PDF

Specialized areas of transplantation immunology Efforts to improve success of transplant procedures Pre-screening for donor-recipient compatibility Use of immunosuppressive drugs Xenogeneic transplantation Blood transfusion Hematopoietic stem cell (HSC) transplantation Transplantation immunology enc...

Specialized areas of transplantation immunology Efforts to improve success of transplant procedures Pre-screening for donor-recipient compatibility Use of immunosuppressive drugs Xenogeneic transplantation Blood transfusion Hematopoietic stem cell (HSC) transplantation Transplantation immunology encompasses a wide range of specialized areas aimed at improving the success of transplant procedures. Let's delve into each of these areas: 1. **Efforts to improve success of transplant procedures**: This encompasses all the strategies and techniques aimed at enhancing the overall success rates of transplantation. These efforts include advancements in surgical techniques, post-operative care, and immune system management to prevent rejection and improve graft survival. 2. **Pre-screening for donor-recipient compatibility**: Pre-screening involves comprehensive evaluations of both the donor and recipient to assess compatibility. This includes histocompatibility testing, which examines genetic markers such as human leukocyte antigens (HLAs) to ensure a closer match between the donor and recipient. The closer the match, the lower the risk of rejection. 3. **Use of immunosuppressive drugs**: Immunosuppressive drugs are essential in transplantation to prevent the recipient's immune system from attacking and rejecting the donor graft. These drugs work by suppressing the 1 immune response, thus reducing the risk of rejection. However, they also increase the recipient's susceptibility to infections and other complications, necessitating careful management and monitoring. 4. **Xenogeneic transplantation**: Xenogeneic transplantation involves the transfer of organs or tissues between different species. For example, xenotransplantation from pigs to humans has been explored as a potential solution to the shortage of human organs for transplantation. However, xenogeneic transplantation faces significant immunological challenges due to the high risk of rejection and the potential for transmission of infectious diseases from the donor species to the recipient. 5. **Blood transfusion**: While not strictly transplantation, blood transfusion involves the transfer of blood or blood products from a donor to a recipient. Immunological considerations are important in blood transfusion to minimize adverse reactions such as hemolytic transfusion reactions and transfusion-related acute lung injury (TRALI). 6. **Hematopoietic stem cell (HSC) transplantation**: HSC transplantation, also known as bone marrow transplantation, involves the transfer of stem cells from a compatible donor to a recipient to treat various hematological disorders, immune deficiencies, and certain cancers. HSC transplantation requires careful matching between donor and recipient to minimize the risk of graft-versus-host disease (GVHD) while maximizing the graft-versus-tumor effect. Each of these specialized areas plays a crucial role in transplantation immunology, contributing to the ongoing efforts to improve the success rates of transplant procedures and ultimately enhance patient outcomes. 1 Mechanisms of action of immunosuppressive drugs Most now in routine use: Delay or treat graft rejection Act to inhibit or kill T lymphocytes Fall into certain categories that target either cell surface or intracellular proteins Immunosuppressive drugs play a crucial role in preventing graft rejection in transplantation procedures. These drugs work through various mechanisms to inhibit or kill T cells, which are a key component of the immune system responsible for recognizing and attacking foreign tissue. Let's delve into the mechanisms of action of immunosuppressive drugs: 1. **Inhibition or killing of T cells**: Immunosuppressive drugs primarily target T cells to prevent them from mounting an immune response against the transplanted tissue. By inhibiting or killing T cells, these drugs reduce the risk of graft rejection. 2. **Cell surface protein targeting**: Some immunosuppressive drugs target cell surface proteins on T cells or antigen-presenting cells (APCs). For example, drugs such as cyclosporine and tacrolimus inhibit calcineurin, a protein phosphatase essential for T cell activation, by binding to cyclophilin and FKBP-12, respectively. This prevents the activation of T cells and subsequent immune response against the graft. 2 3. **Intracellular protein targeting**: Other immunosuppressive drugs target intracellular proteins involved in T cell activation and proliferation. For instance, drugs like mycophenolate mofetil inhibit inosine monophosphate dehydrogenase, an enzyme required for the synthesis of guanosine nucleotides, which are essential for DNA replication in activated T cells. By disrupting nucleotide synthesis, these drugs suppress T cell proliferation. 4. **Interleukin-2 (IL-2) pathway modulation**: IL-2 is a key cytokine involved in T cell activation and proliferation. Some immunosuppressive drugs, such as basiliximab and daclizumab, are monoclonal antibodies that target the IL-2 receptor on activated T cells, preventing IL-2 signaling and subsequent T cell proliferation. 5. **Interference with co-stimulatory pathways**: Co-stimulatory pathways play a critical role in T cell activation and differentiation. Drugs like belatacept inhibit the interaction between CD80/86 on APCs and CD28 on T cells, preventing costimulation and T cell activation. 6. **Modulation of cytokine production**: Certain immunosuppressive drugs, such as corticosteroids, inhibit the production of pro-inflammatory cytokines, including interleukins and tumor necrosis factor-alpha (TNF-α), which are involved in the immune response and graft rejection. Overall, immunosuppressive drugs exert their effects through multiple mechanisms to suppress the immune response and prevent graft rejection in transplantation procedures. However, these drugs may also increase the risk of infections and other complications, underscoring the importance of careful management and monitoring in transplant patients. 2 Mechanisms of action of immunosuppressive drugs (1) Shutdown of IL-2 signaling by inhibiting IL-2 transcription Cyclosporine: Best understood, most important Inhibits calcineurin (activator of IL-2 expression) The first class of immunosuppressive drugs primarily works by inhibiting interleukin-2 (IL-2) signaling, a crucial pathway involved in T cell activation and proliferation. IL-2 is a cytokine produced by activated T cells themselves and plays a pivotal role in driving immune responses, including proliferation and differentiation. One of the most well-understood and widely used drugs in this class is cyclosporine. Cyclosporine works by inhibiting an enzyme called calcineurin. Calcineurin is activated when T cells recognize antigens, leading to downstream signaling events that ultimately result in IL-2 expression. IL-2, in turn, drives T cell proliferation and other immune responses. By blocking calcineurin, cyclosporine prevents the activation of downstream pathways that lead to IL-2 expression. Consequently, the production of IL-2 is reduced or inhibited. Without IL-2 signaling, T cells are not stimulated to proliferate or mount a robust immune response against the transplanted tissue. In summary, cyclosporine and similar drugs in this class exert their immunosuppressive effects by disrupting IL-2 3 signaling, thereby suppressing T cell activation and proliferation, which helps prevent graft rejection in transplantation procedures. 3 Cyclosporine was first effective immunosuppressive drug Fungal peptide Similar for liver transplants Cyclosporine stands as a landmark in the field of transplantation as the first effective immunosuppressive drug. It is considered one of the most important and commonly used drugs in transplantation procedures. Cyclosporine is a cyclic peptide produced by certain fungi, and its discovery revolutionized the field of immunosuppression. By inhibiting the enzyme calcineurin, cyclosporine effectively suppresses the production of IL-2, a key cytokine involved in T cell activation and proliferation. This suppression of IL-2 signaling prevents the robust immune response against transplanted tissue, thereby reducing the risk of graft rejection. The introduction of cyclosporine in 1983 marked a significant milestone in transplantation medicine. The graph depicting the five-year survival rates of cardiac allograft patients demonstrates a notable increase in survival following the introduction and widespread use of cyclosporine. While the survival rates are not 100%, the improvement in outcomes is substantial, highlighting the pivotal role of cyclosporine in enhancing the success of transplantation procedures. 4 Moreover, similar improvements in success rates have been observed in other types of transplants, such as liver transplants, following the introduction of cyclosporine. In summary, cyclosporine remains the primary immunosuppressive drug used in various transplantation procedures, contributing significantly to the improved outcomes and survival rates of transplant patients. 4 Mechanisms of action of immunosuppressive drugs (2) Inhibitors of T cell proliferation 1. Rapamycin inhibits mTOR kinase mTOR promotes cell survival & proliferation in response to IL-2R and TCR activation 2. Antimetabolites Toxins that poison T cell proliferation by various mechanisms mTOR = mammalian target of rapamycin The second class of immunosuppressive drugs targets T cell proliferation, aiming to inhibit the proliferation of T cells that would otherwise mount an immune response against the transplanted tissue. These inhibitors act on different parts of the T cell activation pathway to block the signals that promote proliferation. 1. **Rapamycin**: Rapamycin inhibits a protein called mammalian target of rapamycin (mTOR), which is a kinase responsible for phosphorylating target proteins involved in cell survival and proliferation. When mTOR is activated, it promotes T cell proliferation in response to signals from the IL-2 receptor and the T cell receptor (TCR). By inhibiting mTOR with rapamycin, T cell proliferation is suppressed, thereby reducing the risk of graft rejection. 2. **Antimetabolites**: Antimetabolites, such as thiopurines and mycophenolate, are another class of drugs that inhibit T cell proliferation. These drugs act as toxins, poisoning T cell proliferation through various mechanisms. 5 They target different enzymes or processes involved in nucleotide synthesis, DNA replication, or cell division, ultimately blocking the proliferation of activated T cells. While there are various types of antimetabolites with different mechanisms of action, they all share the common goal of inhibiting T cell proliferation to prevent graft rejection. Regardless of whether inhibition occurs through blocking mTOR activation or poisoning proliferation in different ways, the end result is the same: T cells fail to proliferate in response to antigens from the graft. This suppression of T cell proliferation reduces the likelihood of rejection or delays rejection, thereby promoting the success of transplantation procedures. 5 Mechanisms of action of immunosuppressive drugs (3) Costimulatory blockade Example: CTLA4-Ig prevents costimulation of T cell CD28 by B7 on APCs The third mechanism of action of immunosuppressive drugs involves creating a costimulatory blockade, which interrupts the crucial interaction between antigen-presenting cells (APCs) and T cells that is necessary for T cell activation and proliferation. 1. **Costimulatory blockade**: In the normal activation process, APCs present antigens and express a protein called B7, which binds to the CD28 receptor on T cells, providing a co-stimulatory signal necessary for T cell activation and subsequent IL-2 production. This IL-2 production drives T cell proliferation and the immune response against the transplanted tissue. One example of a drug that creates a costimulatory blockade is CTLA-4 Ig. This drug consists of the binding site of CTLA-4, an inhibitory co-stimulator molecule, recombinantly attached to part of the immunoglobulin (Ig) protein. This modification increases the stability and half-life of the drug. CTLA-4 Ig works by blocking the interaction between B7 on APCs and CD28 on T cells, thereby preventing the co-stimulatory signal necessary for IL-2 production and subsequent T cell proliferation. 6 Overall, various drugs can be used as immunosuppressive agents, but they largely target IL-2 production and T cell proliferation. By inhibiting these processes, the drugs prevent the activation of T cells and the immune response against the transplanted tissue. This suppression of T cell activation and proliferation significantly reduces the risk of rejection, delaying or even preventing it altogether. 6 Other aspects of immunosuppressive protocols Often use anti-inflammatory corticosteroids to block cytokine synthesis or secretion May initially involve combination of drugs w/ different drugs used for maintenance Current protocols more effective for acute rejection than chronic rejection Chronic rejection now typical reason for allograft failure Immunosuppressive therapy increases susceptibility to infections and viral-promoted tumors In addition to immunosuppressive drugs, there are several other aspects of immunosuppressive protocols involved in transplantation procedures: 1. **Use of anti-inflammatory corticosteroids**: Anti-inflammatory corticosteroids are often included in immunosuppressive protocols to mitigate the innate immune response to transplanted tissue. By blocking cytokine synthesis or secretion, corticosteroids reduce inflammation and dampen the immune response, which can prolong the success of the transplant. 2. **Combination therapy**: Immunossuppressive protocols typically involve a combination of drugs, especially during the initial phases of transplantation. Different classes of drugs may be combined to provide comprehensive immunosuppression and reduce the risk of rejection. These combinations may be adjusted over time based on the patient's response and tolerance to the medications. 3. **Maintenance therapy**: After the initial phase of transplantation, maintenance therapy is often continued to 7 provide long-term immunosuppression and prevent graft rejection. This may involve a different combination of drugs compared to the initial induction therapy, tailored to maintain immune suppression while minimizing side effects. 4. **Acute vs. chronic rejection**: Current immunosuppressive protocols are more effective at managing acute rejection, which occurs shortly after transplantation, compared to chronic rejection, which develops gradually over time. Chronic rejection, often involving vascular changes, remains a significant challenge in transplantation medicine, and current protocols may not fully prevent its occurrence. 5. **Increased susceptibility to infections and tumors**: Immunosuppressive therapy significantly increases the patient's susceptibility to infections due to the suppression of the immune system. Additionally, long-term immunosuppression can increase the risk of developing viral-driven tumors, such as certain types of cancers associated with viral infections like HPV. Patients on immunosuppressive drugs require vigilant monitoring for infections and cancerous developments. Overall, immunosuppressive protocols in transplantation involve a multifaceted approach aimed at suppressing the immune response to prevent graft rejection while managing the associated risks and complications, such as infections and tumors. These protocols are continually refined to improve outcomes and minimize adverse effects for transplant recipients. 7 8 Xenogeneic transplantation Interest driven by lack of available human donor tissue and organs => Pigs have “anatomically correct organs” and are readily available Challenges to routine use of pig organs include: Natural Abs in humans that induce hyperacute rejection response => These IgMs recognize specific galactose on glycosylated pig proteins Other poorly understood mechanisms that induce acute rejection response T cell mechanisms similar to those involved in allograft rejection Xenogeneic transplantation, or the transplantation of organs or tissues from one species to another, presents unique challenges and opportunities in the field of transplantation medicine. Here are some key points regarding xenogeneic transplantation: 1. **Interest and rationale**: Xenogeneic transplantation is driven by the shortage of available donor tissue and organs for transplantation in humans. Pigs are often used as a source of xenogeneic organs because their anatomical size is comparable to human organs, and they are readily available for research and potential transplantation. However, utilizing pig organs for transplantation requires overcoming significant immunological barriers. 2. **Challenges**: One major challenge in xenogeneic transplantation is the presence of natural antibodies in humans that induce hyperacute rejection. These antibodies, primarily IgM, recognize specific sugar moieties on glycosylated pig proteins, leading to rapid rejection of the transplanted organ. Additionally, there are other poorly understood mechanisms that contribute to acute rejection responses in xenogeneic transplantation. 9 3. **Immune response**: The human immune system mounts both innate and adaptive immune responses against transplanted xenogeneic organs. T cell-mediated mechanisms, similar to those involved in allograft rejection, play a significant role in xenograft rejection. Understanding and modulating these immune responses are crucial for improving the success of xenogeneic transplantation. 4. **Research focus**: While xenogeneic transplantation has been explored for various organs, such as kidneys, significant research efforts are focused on overcoming immunological barriers to make xenogeneic transplantation a viable option for other types of tissues and organs. These efforts include genetic modifications of donor animals to reduce immunogenicity and the development of immunomodulatory strategies to prevent rejection. 5. **Current status**: Xenogeneic transplantation has made significant progress in preclinical studies, but translating these findings into clinical practice remains challenging. Ongoing research aims to address immunological barriers and improve the long-term viability of xenogeneic grafts in humans. Overall, xenogeneic transplantation holds promise as a potential solution to the shortage of donor organs for transplantation. However, significant hurdles, particularly related to immunological compatibility, must be overcome to realize its clinical potential. Ongoing research in this field is crucial for advancing the understanding and feasibility of xenogeneic transplantation in clinical settings. 9 Blood transfusions are the most common form of transplantation Challenge is immune response to cell surface antigens that differ between individuals ABO is most important alloantigen system for transfusions ABO type depends on carbohydrate chains added to cell surface proteins and lipids Antigen and thus blood type are determined by polymorphic glycosyltransferases Blood transfusions are indeed the most common form of transplantation, and understanding the ABO blood group system is crucial for ensuring compatibility between donors and recipients. Here's an overview of the ABO blood group system and its relevance to blood transfusions: 1. **ABO blood group system**: The ABO blood group system is based on the presence or absence of specific carbohydrate chains, known as oligosaccharides, on the surface of red blood cells. These oligosaccharides determine the ABO blood types: A, B, AB, and O. 2. **Antigens and antibodies**: Each blood type has characteristic antigens on the surface of red blood cells. For example, individuals with type A blood have A antigens, type B blood have B antigens, type AB blood have both A and B antigens, and type O blood have neither A nor B antigens. Corresponding antibodies against the antigens that are not present on the individual's red blood cells are naturally produced in the plasma. 3. **Compatibility and transfusions**: A crucial aspect of blood transfusions is ensuring compatibility between the 10 donor's blood type and the recipient's blood type to prevent adverse reactions. For example: - Individuals with type A blood can receive blood from type A or type O donors. - Individuals with type B blood can receive blood from type B or type O donors. - Individuals with type AB blood can receive blood from any blood type (A, B, AB, or O) donors. - Individuals with type O blood (universal donors) can only receive blood from type O donors. 4. **Glycosyltransferase enzymes**: The presence or absence of specific glycosyltransferase enzymes, determined by an individual's genetic makeup, dictates the addition of particular carbohydrate groups to the basic oligosaccharide structure. These enzymes are encoded by the ABO gene located on chromosome 9. 5. **Allelic variation**: The alleles inherited from both parents determine an individual's ABO blood type. For example: - Individuals with the A allele produce the enzyme responsible for adding N-acetyl-galactosamine to the basic oligosaccharide structure, resulting in the A antigen. - Individuals with the B allele produce the enzyme responsible for adding galactose to the basic structure, resulting in the B antigen. - Individuals with both A and B alleles (AB blood type) produce both enzymes, resulting in the presence of both A and B antigens. - Individuals with the O allele lack functional glycosyltransferase enzymes, leading to the absence of A and B antigens. Understanding the ABO blood group system and ensuring compatibility between donors and recipients are essential for safe and effective blood transfusions, minimizing the risk of adverse reactions. 10 Individuals who don’t express a particular AB antigen produce natural IgM antibodies against that antigen Indeed, individuals who do not express a particular ABO blood group antigen naturally produce antibodies against that antigen. These antibodies, known as natural IgM antibodies, are pre-existing and are part of the innate immune response. Here's how it works for each blood type: 1. **Type A individuals**: Type A individuals naturally produce anti-B antibodies (IgM) because they do not express the B antigen on their red blood cells. 2. **Type B individuals**: Type B individuals naturally produce anti-A antibodies (IgM) because they lack the A antigen on their red blood cells. 3. **Type AB individuals**: Type AB individuals express both A and B antigens on their red blood cells and, therefore, do not produce natural anti-A or anti-B antibodies. 4. **Type O individuals**: Type O individuals do not express A or B antigens on their red blood cells, so they 11 naturally produce both anti-A and anti-B antibodies (IgM). This phenomenon has implications for blood transfusion compatibility. Individuals with type AB blood (universal recipients) can receive blood from any blood type because they do not produce anti-A or anti-B antibodies. However, individuals with type O blood (universal donors) can only donate to individuals of any blood type because they produce both anti-A and anti-B antibodies, which can cause adverse reactions if transfused into individuals expressing A or B antigens on their red blood cells. Understanding the natural antibodies produced in response to ABO blood group antigens is crucial for determining blood transfusion compatibility and ensuring safe transfusions without triggering adverse immune responses. 11 Consequences of ABO donor recipient mismatch Produces rapid and strong “transfusion reaction” Pre-existing IgMs bind to “foreign” antigen on donor cells => activate complement in vasculature => induce phagocytosis via opsonization in liver and spleen Resulting hemolysis of RBCs releases large amount of hemoglobin => toxic to kidneys Innate response = fever, shock, disseminated coagulation via cytokine storm Reactions are generally serious and may be fatal When there is an ABO donor-recipient mismatch in blood transfusion, it can lead to severe consequences known as transfusion reactions. Here's a breakdown of what happens during an ABO incompatibility: 1. **Transfusion reaction**: The recipient, for example, a person with type O blood, receives a transfusion of blood that is type AB or type A. This leads to the activation of pre-existing IgM antibodies present in the recipient's plasma against the foreign A or B antigens on the donor's red blood cells. 2. **Activation of complement**: The binding of antibodies to the foreign antigens on the donor's red blood cells activates the complement system in the recipient's vasculature. Complement activation leads to the recruitment of inflammatory cells and the formation of membrane attack complexes, causing damage to the red blood cells. 3. **Hemolysis**: The activation of complement and subsequent inflammatory response leads to the destruction of the donor's red blood cells, a process known as hemolysis. Hemolysis results in the release of large amounts of hemoglobin into the bloodstream. 12 4. **Toxicity to kidneys**: The released hemoglobin is toxic to the kidneys, impairing their function and potentially leading to kidney damage or failure. 5. **Systemic inflammatory response**: The transfusion reaction triggers a systemic inflammatory response, characterized by fever, shock, and disseminated intravascular coagulation (DIC). DIC is a condition where blood clotting factors are consumed, leading to widespread clot formation throughout the vasculature. 6. **Cytokine storm**: The inflammatory response induces the production of cytokines by various cell types throughout the body, leading to further amplification of the immune response and exacerbation of systemic symptoms. Transfusion reactions due to ABO incompatibility can be severe and life-threatening if not promptly recognized and treated. The historical challenges faced during the early days of blood transfusion highlight the importance of accurately determining blood types and ensuring compatibility between donors and recipients to prevent such adverse reactions. 12 HSC Transplantation Treats lethal diseases caused by defects hemopoietic lineage (e.g., leukemias) Sources: bone marrow or blood (peripheral or cord) Requires elimination of host HSC’s prior to transplant Challenges: Infection Rejection Graft vs. Host Disease (GVHD): donated T cells attack host antigens Immunodeficiency: failure to generate new immune system Hematopoietic Stem Cell (HSC) transplantation, also known as bone marrow transplantation, involves the transfer of hematopoietic stem cells from a donor to a recipient to treat various diseases, particularly those affecting the blood and immune system. Here's an overview of HSC transplantation: 1. **Indications**: HSC transplantation is typically used to treat diseases where there is a malfunction or malignancy of the recipient's hematopoietic stem cells. This includes conditions like leukemia, lymphoma, and certain genetic disorders affecting the blood or immune system. 2. **Source of stem cells**: Hematopoietic stem cells can be obtained from various sources, including bone marrow, peripheral blood, and umbilical cord blood. Historically, bone marrow was the primary source, but nowadays, there's a shift towards using peripheral blood or umbilical cord blood due to their accessibility and ease of collection. 3. **Procedure**: The procedure involves first destroying the recipient's existing hematopoietic stem cells, often 13 through chemotherapy or radiation therapy. This step aims to eliminate any cancerous or dysfunctional cells. Then, the donor's stem cells are infused into the recipient's bloodstream, where they migrate to the bone marrow and begin to regenerate the blood and immune system. 4. **Challenges and risks**: - **Infection**: As the recipient's immune system is compromised during the transplant process, there is an increased risk of infections. - **Rejection**: There's a possibility that the recipient's immune system may recognize the donor's stem cells as foreign and reject them. - **Graft-versus-host disease (GVHD)**: In GVHD, the donor's immune cells attack the recipient's tissues, leading to inflammation and organ damage. This condition can be severe and even life-threatening. - **Immunodeficiency**: In some cases, the transplant may not be successful in restoring normal immune function, leaving the recipient susceptible to infections and other complications. 5. **Outcome and follow-up**: The success of HSC transplantation depends on various factors, including the compatibility of the donor and recipient, the underlying disease being treated, and the management of complications posttransplantation. Patients undergoing HSC transplantation require close monitoring and may need ongoing immunosuppressive therapy to prevent rejection or GVHD. In summary, HSC transplantation is a potentially curative treatment for certain blood and immune disorders, but it carries significant risks and requires careful management to ensure successful outcomes. 13