lecture 26 studyguide- immunology.pdf

Transplantation Immunology Transplantation: Þ transferring cells, tissues, or organs from one individual into a different individual Þ now common practice in clinical medicine Transplanted material = “graft” Individual who provides the graft = “donor” Individual who receives the graft = “recipient”...

Transplantation Immunology Transplantation: Þ transferring cells, tissues, or organs from one individual into a different individual Þ now common practice in clinical medicine Transplanted material = “graft” Individual who provides the graft = “donor” Individual who receives the graft = “recipient” or “host” This transcript appears to be from a lecture or discussion on transplantation immunology, focusing on the basics of transplants, related terminology, and the common practices in clinical medicine. Let's break down the key points in detail: 1. **Introduction to Transplantation Immunology**: The speaker introduces the topic as focusing on the basics of transplants, including terminology, definitions, and general concepts. They mention that the discussion will continue into the next session, where they'll explore how these basic concepts can be applied to improve transplant success rates. 2. **Definition of Transplantation**: Transplantation, as defined in this discussion, involves the transfer of cells, tissues, or organs from one individual to another. It's noted that while they'll stick to this definition primarily, there are other contexts where transplantation might be interpreted differently. 3. **Commonality of Transplantation in Clinical Medicine**: The speaker highlights that transplantation has 1 become a routine procedure in clinical medicine. Major medical centers typically have specialized units for conducting transplants, indicating the widespread adoption of this medical practice. 4. **Research and Advancements**: The speaker mentions that a significant amount of research has been dedicated to transplantation. They hint at cutting-edge developments in the field, possibly referring to recent advancements or breakthroughs that could impact transplant procedures and outcomes. 5. **Terminology**: The speaker clarifies the terminology associated with transplantation. They define the "graft" as the transplanted material, which can include cells, tissues, or organs. The individual providing the graft is referred to as the "donor," while the recipient receiving the graft is called the "recipient" or the "host." The terms "recipient" and "host" are noted to be used interchangeably. 6. **Use of Terminology**: The speaker emphasizes the importance of becoming comfortable with the terminology used in transplantation immunology. They mention that different figures or sources may use slightly different terms, but they essentially refer to the same concepts. Overall, this transcript serves as an introductory discussion on transplantation immunology, covering basic definitions, terminology, and the significance of transplantation in clinical medicine. It sets the stage for further exploration of the topic, particularly focusing on advancements and strategies to enhance transplant success rates. 1 Transplantation Immunology The field of transplantation immunology asks: 1. how does the recipient's immune system recognize and attack grafted tissue? 2. how can immune response be controlled to improve transplant success? Knowledge mostly comes from: Experiments with mice Clinical observations Medical interventions The transcript delves into the fundamental questions and practical applications within the field of transplantation immunology, offering a detailed explanation: 1. **Types of Questions in Transplantation Immunology**: - The speaker introduces two main categories of questions: fundamental questions and clinical/applied questions. These categories help organize the discussion for the current session and what will be covered in the following session. - Fundamental questions focus on understanding how the recipient's immune system identifies and responds to transplanted tissues. This involves the distinction between "self" and "foreign" within the immune system. - Clinical or applied questions aim to address practical aspects, such as controlling the immune response from the donor side to prevent rejection and improve transplant success rates. 2. **Recognition and Rejection Mechanisms**: - The discussion emphasizes the importance of understanding how the immune system recognizes and potentially 2 rejects transplanted tissue. Specific proteins within the grafted tissue play a key role in triggering the recipient's immune response. 3. **Sources of Understanding in Transplantation Immunology**: - The speaker outlines various sources contributing to our understanding of transplantation immunology. - Experiments with mice are highlighted as a crucial aspect of research, as mice serve as classic model organisms for studying mammalian systems. However, the speaker notes that while mice provide valuable insights, they are not always perfect models, so information from other sources is also essential. - Clinical observations play a significant role, where successful and unsuccessful transplant procedures offer valuable insights into factors influencing outcomes. - Medical interventions, including pharmaceutical approaches (such as drugs) and procedural techniques (such as organ preparation and storage methods), also contribute to our understanding of transplantation immunology. 4. **Ethical Considerations**: - The speaker briefly touches on ethical considerations, particularly regarding experiments involving mice compared to human transplants. They emphasize the importance of ethical conduct in research and the potential ethical challenges associated with certain types of experiments. In summary, the transcript provides an overview of the key questions, sources of knowledge, and ethical considerations within transplantation immunology. It sets the stage for further exploration into the mechanisms of immune recognition, rejection, and strategies for improving transplant success. 2 Transplant Basics Types of transplants: Solid organs Blood (transfusion) Hematopoietic stem cells Major challenge is recipient’s immune response to the grafted tissue => Leads to death of donated tissue (rejection) The transcript provides an overview of the basics of transplantation, focusing on three major categories: solid organs, blood transfusions, and hematopoietic stem cell (HSC) transplants. Let's break down the key points: 1. **Solid Organ Transplants**: - The speaker introduces solid organ transplants, highlighting data from the United Network for Organ Sharing (UNOS), which shows the distribution of organ transplants, with kidneys, livers, and hearts being the most common. - They emphasize that blood transfusions also fall under the category of transplants, as they involve transferring cells from one individual to another. - The speaker notes that blood transfusions are among the most common types of transplants, with a deep understanding of blood chemistry derived from clinical observations. 2. **Hematopoietic Stem Cell Transplants**: - The discussion moves to hematopoietic stem cell (HSC) transplants, commonly known as bone marrow or cord 3 blood transplants. - The goal of these transplants is to provide healthy stem cells to the recipient, which can then replace malfunctioning or non-functioning stem cells in the recipient's bone marrow. - The speaker acknowledges the relative success of HSC transplants compared to solid organ transplants. 3. **Challenges in Transplantation**: - The central challenge in transplantation, as highlighted by the speaker, is the potential rejection of the transplanted tissue by the recipient's immune system. - Rejection occurs when the recipient's immune system recognizes the transplanted tissue as foreign and attacks it, leading to the death of the transplanted tissue. - The speaker notes that rejection is almost inevitable in any transplant scenario, except in the case of identical twins, where rejection is less likely. - The goal in transplantation is to delay rejection for as long as possible, allowing the recipient to live a relatively normal life. Overall, the transcript provides an overview of the different types of transplants, their challenges, and the goals of transplantation, setting the stage for further discussion on strategies to address rejection and improve transplant outcomes. 3 Transplant Vocabulary (medical context) Experimental context has additional terminology Allogeneic graft (allograft*): between two genetically different individuals of same species Xenogeneic graft (xenograft): between individuals of different species Alloantigens: molecules recognized as foreign in an allograft Xenoantigens: molecules recognized as foreign in a xenograft Alloreactive: lymphocytes and antibodies that react with alloantigens Xenoreactive: lymphocytes and antibodies that react with xenoantigens * Primary focus of lecture content The transcript introduces vocabulary relevant to the medical context of transplantation, focusing on terms used to describe the relationship between individuals, antigens, and immune system components. Let's break down the key terms and concepts: 1. **Allogeneic Graft (Allograft)**: - An allogeneic graft refers to tissue or organs transplanted between genetically different individuals of the same species. - Allografts are common in medical transplantation procedures, where organs or tissues from a donor are transferred to a recipient. - Correspondingly, allogeneic antigens are molecules recognized as foreign in the allograft. These antigens may trigger an immune response in the recipient. 2. **Xenogeneic Graft (Xenograft)**: - A xenogeneic graft involves the transfer of tissue or organs between individuals of different species. 4 - Xenografts are less common in clinical transplantation but are still studied in experimental contexts. - Xenogeneic antigens are molecules recognized as foreign in the xenograft. The immune system of the recipient may react to these antigens. 3. **Reactive Lymphocytes and Antibodies**: - Reactive lymphocytes and antibodies are components of the immune system that respond to foreign antigens present in the transplanted tissue. - In the case of allografts, reactive lymphocytes and antibodies react with allogeneic antigens, while in xenografts, they react with xenogeneic antigens. 4. **Importance of Understanding Vocabulary**: - The speaker emphasizes the importance of understanding these terms in the medical context of transplantation. - By using specific terminology, medical professionals can accurately describe the relationship between donor and recipient, as well as the immune response to the transplanted tissue. 5. **Research Paper Three**: - The speaker references a research paper (presumably titled "Research Paper Three") that likely provides additional information or context related to transplantation, possibly focusing on xenografts or other experimental aspects. - This paper is intended to give students experience in dealing with transplantation terminology and concepts. Overall, the transcript provides a brief overview of vocabulary related to transplantation, focusing on the types of grafts, antigens involved, and immune system responses. Understanding these terms is essential for discussing and studying transplantation in the medical field. 4 Innate immune responses to grafts Important but not primary role in responding to transplanted tissue Surgical procedure Ischemic damage (reduced blood and oxygen supply) Cell dysfunction and death DAMPS produced in the graft Innate immune responses by host and donor cells Some innate responses directly kill donor cells Some activate APCs to promote adaptive responses The transcript delves into the innate immune responses to grafts, focusing on the initial reactions of the recipient's immune system to transplanted tissue. Let's break down the key points: 1. **Introduction to Immune Responses to Grafts**: - The speaker outlines the importance of understanding how the recipient's immune system responds to transplanted tissue, both from the same species (allograft) and from different species (xenograft). - They note that while the innate immune system plays a critical role in responding to grafts, it is not the primary driver of attacking grafted tissue. Instead, the adaptive immune system takes on this primary role. 2. **Innate Immune System Response**: - The speaker discusses the initial response of the innate immune system to transplanted tissue. - Surgery involved in transplantation creates damage to tissues, leading to reduced blood and oxygen supply to cells, termed ischemic damage. - Ischemic damage results in cell dysfunction and death, leading to the production of damage-associated 5 molecular patterns (DAMPs). DAMPs are molecules produced as a result of cellular damage or stress. - The presence of DAMPs triggers an inflammatory response in the region of the transplant, involving cells such as neutrophils and macrophages. These cells contribute to inflammation and tissue repair processes. 3. **Role of Adaptive Immune System**: - While the innate immune response is initiated by surgery and ischemic damage, it also activates the adaptive immune system. - Antigen-presenting cells (APCs) in the region of the transplant display antigens derived from the graft, leading to the activation of adaptive immune responses in the recipient. - The adaptive immune response, driven by T cells and B cells, becomes the primary driver of attacking grafted tissue and potentially causing rejection. 4. **Management of Immune Responses**: - The speaker mentions the use of drugs and other interventions to suppress immune responses in transplantation. These interventions aim to mitigate the adaptive immune response and improve the success of transplants. Overall, the transcript provides an overview of the innate immune responses to grafts, highlighting the role of ischemic damage, DAMPs, inflammation, and the subsequent activation of adaptive immune responses. Understanding these processes is essential for managing immune responses in transplantation and improving transplant success rates. 5 Adaptive immune responses to grafts Primary reason for rejection of transplanted tissue Alloantigens induce both cellular and humoral immune responses Most alloantigens are proteins encoded by polymorphic genes that differ among individuals - these genes are codominant in each individual MHC molecules are: most important alloantigens responsible for strong and rapid transplant rejection so polymorphic that no two individuals will inherit the same ones This transcript discusses the adaptive immune responses to grafts, specifically focusing on the recognition of alloantigens by the recipient's immune system. Let's break down the key points: 1. **Introduction to Adaptive Immune Responses**: - The speaker shifts the focus to the adaptive immune response to grafts, noting that alloantigens are the primary reason for the rejection of transplanted tissue. - Alloantigens are antigens present in the donated tissue that are recognized by the recipient's immune system, leading to cellular and humoral immune responses. 2. **Description of Alloantigens**: - Alloantigens are described as proteins encoded by polymorphic genes that differ among individuals. - These genes, which encode alloantigens, are highly variable and prevalent in each individual's genome. - The speaker poses a question to identify which type of molecules alloantigens are. The correct answer is MHC proteins. 6 3. **Major Histocompatibility Complex (MHC) Proteins**: - MHC proteins, or major histocompatibility complex proteins, are discussed as the primary alloantigens recognized by the adaptive immune response. - MHC proteins were initially identified in studies involving mouse transplants, where their compatibility or lack thereof influenced transplant success or rejection. - The variability and polymorphism of MHC proteins make it unlikely for two individuals to have identical MHC profiles, except for identical twins. 4. **Importance of MHC Compatibility**: - The transcript emphasizes the critical role of MHC proteins in determining transplant success. - The closer the match between the MHC proteins of the donor and recipient, the lower the likelihood of rejection. - MHC proteins play a significant role in tissue compatibility, and their variability is a key consideration in transplantation. Overall, the transcript provides insight into the adaptive immune response to grafts, focusing on the recognition of alloantigens, particularly MHC proteins, and the importance of compatibility in transplant success. Understanding the role of MHC proteins is essential for optimizing transplant outcomes and reducing the risk of rejection. 6 Host T cells (alloreactive T cells) recognize alloantigens through direct and indirect mechanisms Rejection Host T cells recognize intact, unprocessed MHC I and II proteins with bound peptide on donor APCs Host CD4+ and CD8+ T cells differentiate into helper T cells and CTLs, respectively This transcript explains the direct mechanism by which host T cells, also known as alloreactive T cells, recognize alloantigens presented by donor cells. Here's a breakdown of the key points: 1. **Direct Recognition of Alloantigens**: - The transcript focuses on how T cells of the host immune system recognize alloantigens from the donor tissue. - Host T cells recognize intact, unprocessed MHC class I and class II proteins with bound peptides on donor antigen-presenting cells (APCs). - These donor APCs, particularly dendritic cells, are part of the graft and accompany the transplanted tissue. - Alloreactive host T cells, including CD4+ and CD8+ T cells, recognize peptides presented by the donor MHC on dendritic cells. - This recognition activates the host T cells, leading to immune responses against the donor tissue. 2. **Activation of Host T Cells**: - Upon recognition of alloantigens, host CD4+ T cells differentiate into helper T cells, producing cytokines that 7 promote the activation, differentiation, and specialization of CD8+ T cells into effector cytotoxic T lymphocytes (CTLs). - Effector CTLs then recognize and kill graft tissue cells presenting alloantigens, leading to the destruction of the transplanted cells. - The direct presentation of alloantigens by donor dendritic cells to host T cells bypasses the need for antigen processing by host APCs, making it a rapid and efficient mechanism of immune recognition. 3. **Importance of MHC Compatibility**: - The transcript underscores the significance of MHC proteins in allorecognition, as they are the primary alloantigens recognized by host T cells. - Mismatch between donor and recipient MHC proteins increases the likelihood of alloreactive T cell responses, leading to graft rejection. 4. **Consequences of Alloreactive T Cell Responses**: - The activation of alloreactive T cells and subsequent killing of graft tissue cells pave the way for graft rejection. - Direct recognition of alloantigens by host T cells sets in motion immune responses that target and eliminate the transplanted tissue. Overall, the transcript provides a detailed explanation of the direct mechanism by which host T cells recognize and respond to alloantigens presented by donor cells, leading to graft rejection in transplantation. Understanding these mechanisms is crucial for devising strategies to minimize rejection and improve transplant outcomes. 7 Host T cells (alloreactive T cells) recognize alloantigens through direct and indirect mechanisms Allogeneic MHCs from graft processed by host APCs and donor MHC-specific peptides are presented by host MHCs In the transcript, the indirect mechanism by which alloreactive T cells recognize alloantigens is discussed. Here's a detailed breakdown: 1. **Overview of Indirect Recognition**: - The indirect mechanism involves the presentation of donor MHC molecules (alloantigens) by host APCs to host T cells. - Unlike the direct mechanism, where donor APCs present alloantigens directly to host T cells, in the indirect pathway, the alloantigens are processed and presented by host APCs. 2. **Process of Indirect Recognition**: - Host dendritic cells take up and process MHC molecules from the donated tissue cells. - These processed donor MHC molecules are then presented by host MHC molecules on the surface of host dendritic cells. 8 - Alloreactive CD4+ T cells, recognizing peptides from the donor MHC, become activated when they encounter the donor MHC peptides presented by host dendritic cells. 3. **Outcomes of Indirect Recognition**: - Upon activation, CD4+ T cells have two primary outcomes: - Interaction with B cells: CD4+ T cells interact with B cells, leading to B cell activation, proliferation, differentiation, affinity maturation, and isotype switching. This results in the production of antibodies that recognize the donor MHC peptides. - Induction of inflammation: CD4+ T cells can also drive inflammation directly or indirectly through macrophages. They recognize donor MHC peptides presented by host macrophages, leading to the initiation of the inflammatory response in the graft tissue. 4. **Consequences of Indirect Recognition**: - The activation of alloreactive T cells through the indirect pathway results in the activation of the adaptive immune system of the host. - This activation leads to various effector mechanisms, including antibody production and inflammation, ultimately causing damage to the transplanted tissue. - Indirect recognition, similar to the immune response against pathogens, involves the activation of T cells by APCs presenting processed alloantigens. 5. **Comparison with Pathogen Response**: - The transcript draws a parallel between the indirect mechanism of alloantigen recognition and the mechanism used by T cells to combat pathogens. - Just as T cells respond to pathogen-derived antigens presented by APCs, alloreactive T cells respond to donor MHC peptides presented by host APCs in the indirect pathway. Overall, the indirect recognition pathway illustrates a key mechanism by which alloreactive T cells recognize alloantigens and initiate immune responses against transplanted tissue. Understanding this mechanism is crucial for developing strategies to modulate alloimmune responses and improve transplant outcomes. 8 Activation of alloreactive T cells Proliferation Differentiation Effector functions Also, activation of alloreactive B cells leads to generation of alloantibodies that recognize graft antigens Alloantibodies most frequently recognize donor Class I and Class II MHC molecules Alloreactive antibodies engage effector mechanisms => complement, Fc receptor-mediated Endothelial cells express Class I MHC => Graft vasculature is prime target The transcript describes the process of activation of alloreactive T cells in response to transplanted tissue, focusing on the direct and indirect pathways. Here's a breakdown of the key points: 1. **Activation of Alloreactive T Cells**: - The figure depicts the journey of donor tissue, particularly a kidney, and the subsequent immune response triggered by the transplanted organ. - Activation of alloreactive T cells involves the recognition of alloantigens, primarily MHC proteins from the donated tissue, by host immune cells. 2. **Direct and Indirect Pathways**: - In the direct pathway, donor dendritic cells, which accompany the transplanted tissue, present alloantigens directly to host T cells, leading to their activation. - In the indirect pathway, host dendritic cells within the transplanted tissue take up and process donor MHC molecules, presenting peptides from these molecules to host T cells. 9 3. **Sensitization and Activation**: - Sensitization occurs when host dendritic cells present processed donor MHC peptides to naive T cells in the draining lymph nodes. - This leads to the activation and proliferation of alloreactive T cells, which differentiate into effector T cells, including CD4+ helper T cells and CD8+ cytotoxic T cells. 4. **Effector Functions**: - The activated effector T cells leave the lymph nodes and migrate back to the transplanted tissue, where they encounter and respond to alloantigens. - CD8+ cytotoxic T cells directly kill graft tissue cells presenting alloantigens, while CD4+ helper T cells induce inflammation and cytokine production, further damaging the transplanted tissue. 5. **Role of Antibodies**: - Alloreactive B cells are also activated, leading to the production of alloantigen-specific antibodies. - These antibodies, particularly those targeting MHC proteins on the donated tissue, recruit complement proteins and immune cells like natural killer cells, contributing to tissue damage and rejection. 6. **Targeting of Graft Vasculature**: - Notably, the vasculature of the transplanted tissue, especially the endothelial cells lining blood vessels, is a primary target of antibody-mediated effector mechanisms. - Damage to the graft vasculature compromises blood flow to the transplanted tissue, exacerbating tissue rejection. Overall, the activation of alloreactive T cells, along with the production of alloantigen-specific antibodies, orchestrates an immune response against transplanted tissue, leading to tissue damage and rejection. Understanding these pathways is crucial for developing strategies to modulate immune responses and improve transplant outcomes. 9