14.1 Histocompatibility and graft rejection
2 min read•july 25, 2024
Histocompatibility antigens play a crucial role in transplantation. These unique cell surface proteins trigger immune responses against foreign tissue, leading to graft rejection. Understanding their function is key to successful organ transplants.
genes are central to transplantation. Their high variability between individuals makes finding compatible donors challenging. Matching MHC types between donor and recipient significantly improves graft survival rates.
Histocompatibility and Graft Rejection
Role of histocompatibility antigens
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- Histocompatibility antigens act as unique cell surface proteins varying between individuals
- Function in graft rejection by triggering recipient's immune response against transplanted tissue
- Types include major histocompatibility complex (MHC) and minor histocompatibility antigens
- Recognition mechanisms involve T cell receptors binding to MHC-peptide complexes activating leading to graft rejection
MHC in transplantation
- MHC genes located on chromosome 6 in humans exhibit high polymorphism
- MHC classes: Class I expressed on all nucleated cells, Class II on antigen-presenting cells
- Human Leukocyte Antigens (HLA) represent human version of MHC
- Mismatch between donor and recipient MHC increases rejection risk while matching improves graft survival
- MHC molecules present peptides to T cells essential for immune recognition and response
Types of graft rejection
- occurs within minutes to hours post-transplantation mediated by preformed antibodies against donor antigens resulting in rapid graft failure
- develops days to weeks after transplantation involving T cell-mediated response against donor antigens characterized by inflammation and tissue damage
- occurs months to years post-transplantation involving both cellular and humoral immune responses leading to progressive fibrosis and loss of graft function
- Cellular mechanisms:
- Cytotoxic T lymphocytes directly kill donor cells
- Helper T cells activate other immune cells
- Humoral mechanisms involve antibodies produced against donor antigens and complement activation leading to tissue damage
HLA typing for compatibility
- HLA typing methods include serological testing and DNA-based techniques (PCR, sequencing)
- Matching criteria focus on six major HLA antigens: HLA-A, B, and DR (two of each) with higher degree of matching correlating with better outcomes
- Applications include solid organ transplantation and hematopoietic stem cell transplantation
- Cross-matching detects preformed antibodies against donor HLA preventing hyperacute rejection
- Importance varies by transplant type with kidney transplants requiring crucial HLA matching for long-term graft survival while heart and lung transplants emphasize less on HLA matching due to time constraints
- Unrelated donor registries facilitate finding matched donors for patients without related donors
- Emerging technologies like next-generation sequencing enable high-resolution HLA typing and epitope matching for improved compatibility assessment
Key Terms to Review (21)
Acute rejection: Acute rejection is a type of immune response that occurs when the transplanted tissue or organ is recognized as foreign by the recipient's immune system, typically happening within days to weeks after transplantation. This process involves the activation of T cells and the production of antibodies against the transplanted material, leading to inflammation and damage to the graft. Understanding acute rejection is crucial for managing transplant outcomes and emphasizes the importance of histocompatibility and the need for immunosuppression.
Allograft: An allograft is a type of transplant where tissue or an organ is taken from one individual and transplanted into another individual of the same species but with a different genetic makeup. This process is crucial in medical procedures like organ transplants, but it poses risks of graft rejection due to differences in histocompatibility, leading to the recipient's immune system recognizing the transplanted tissue as foreign.
Autograft: An autograft is a type of tissue graft that is taken from one part of an individual's body and transplanted to another site on the same person. This method is often used in surgeries, particularly in reconstructive procedures, as it minimizes the risk of rejection and complications associated with foreign tissue.
B cells: B cells are a type of white blood cell that plays a crucial role in the adaptive immune response by producing antibodies. They originate from hematopoietic stem cells in the bone marrow and are essential for recognizing and responding to specific pathogens, thereby providing long-lasting immunity.
Calcineurin inhibitors: Calcineurin inhibitors are a class of immunosuppressive drugs that block the activity of calcineurin, an enzyme crucial for activating T-cells in the immune response. By inhibiting this enzyme, these drugs prevent T-cells from producing interleukin-2 (IL-2), which is essential for T-cell proliferation and activation. This mechanism is particularly relevant in the context of organ transplantation, as it helps reduce the risk of graft rejection and ensures better graft acceptance.
Cell-mediated immunity: Cell-mediated immunity is a type of adaptive immune response that primarily involves T cells in recognizing and responding to infected or abnormal cells. This immune mechanism is crucial for defending against intracellular pathogens like viruses and certain bacteria, as well as for the elimination of cancerous cells. The activation and differentiation of T cells, the various subsets they form, and their roles in vaccination, histocompatibility, and transplant rejection are all important aspects of understanding how cell-mediated immunity operates.
Chronic rejection: Chronic rejection is a long-term immune response that occurs after transplantation, where the recipient's immune system gradually damages the transplanted tissue or organ over time. This type of rejection often manifests as a slow decline in the function of the graft and is usually mediated by a combination of cellular and humoral immune mechanisms, making it different from acute rejection, which happens more rapidly. Understanding chronic rejection involves recognizing its relationship with histocompatibility, the various types of transplant rejection, and the importance of immunosuppression to minimize its effects.
Dendritic Cells: Dendritic cells are a type of immune cell that play a crucial role in the body's immune response by capturing, processing, and presenting antigens to T cells. These cells serve as a bridge between the innate and adaptive immune systems, facilitating the activation of T cells and promoting the development of adaptive immunity.
Graft-versus-host disease: Graft-versus-host disease (GVHD) is a serious condition that occurs when donor immune cells attack the recipient's tissues following a transplant. This reaction typically arises after allogeneic transplants, where the donor and recipient are genetically different, leading to complications in the recipient's immune system due to mismatched histocompatibility antigens. GVHD highlights the significance of histocompatibility in organ transplants and is one of the primary forms of transplant rejection that can impact patient outcomes.
Human leukocyte antigen (HLA): Human leukocyte antigen (HLA) refers to a group of proteins found on the surface of cells that play a critical role in the immune system by helping the body recognize foreign substances. These proteins are key components of the major histocompatibility complex (MHC) and are crucial for histocompatibility, which is the ability of tissues to be accepted or rejected during transplantation. Understanding HLA is essential for assessing graft compatibility and preventing rejection during organ transplants.
Humoral Immunity: Humoral immunity is a vital component of the immune system that involves the production of antibodies by B cells to identify and neutralize pathogens like bacteria and viruses. This type of immunity is crucial for recognizing foreign antigens and facilitating their elimination through various mechanisms, connecting deeply with other immune functions such as T cell activation and the development of vaccines.
Hyperacute rejection: Hyperacute rejection is an immediate and severe immune response that occurs within minutes to hours after transplantation, primarily due to pre-existing antibodies in the recipient that target the donor's antigens. This type of rejection is primarily associated with incompatible blood group or human leukocyte antigen (HLA) mismatches, highlighting the critical role of histocompatibility in successful graft acceptance. Understanding hyperacute rejection provides insights into the types of transplant rejections and the importance of immunosuppression strategies to prevent such rapid and destructive responses.
Major histocompatibility complex (MHC): The major histocompatibility complex (MHC) is a set of cell surface proteins essential for the immune system to recognize foreign molecules. MHC molecules play a critical role in antigen presentation, allowing T cells to identify and respond to pathogens. They also determine compatibility between donors and recipients in organ transplantation, highlighting their significance in both immune recognition and graft rejection.
Monoclonal antibodies: Monoclonal antibodies are laboratory-produced molecules engineered to bind specifically to target antigens, such as proteins on the surface of cells. These antibodies are derived from a single clone of immune cells and are designed to recognize only one specific epitope, making them incredibly useful in various biomedical applications, including diagnostics, therapeutics, and research.
Mouse model: A mouse model is a laboratory mouse that has been genetically modified or selectively bred to study specific human diseases or biological processes. These models are essential tools in biomedical research, allowing scientists to investigate the mechanisms of disease, test potential treatments, and evaluate drug efficacy in a living organism that shares significant genetic similarities with humans.
Paul Terasaki: Paul Terasaki is a renowned immunologist known for his groundbreaking work in transplant immunology, particularly in the development of techniques for organ transplantation and the understanding of histocompatibility. His research significantly advanced the field by focusing on the role of human leukocyte antigens (HLAs) in graft rejection and acceptance, paving the way for more successful transplant outcomes.
Pig-to-primate model: The pig-to-primate model is a research framework that involves the use of genetically modified pigs to study organ transplantation and immune response in primates, including humans. This model serves as an innovative approach to address the challenges of organ shortage and rejection by examining the histocompatibility issues associated with xenotransplantation, where organs from one species are transplanted into another.
Sir Peter Medawar: Sir Peter Medawar was a British biologist and Nobel Prize winner known for his pioneering work in the field of transplant immunology and the understanding of graft rejection. He is recognized for his contributions that laid the foundation for our understanding of how the immune system responds to foreign tissues, which is crucial for successful organ transplants. Medawar's work not only advanced scientific knowledge but also had significant implications for clinical practices in organ transplantation.
T cells: T cells, or T lymphocytes, are a type of white blood cell that plays a central role in the adaptive immune response. They originate from hematopoietic stem cells in the bone marrow but mature in the thymus, where they develop the ability to recognize specific antigens presented by other cells. T cells are crucial for cell-mediated immunity, helping to eliminate infected or cancerous cells and orchestrating the immune response.
Tolerance: Tolerance refers to the immune system's ability to recognize self-antigens and avoid an immune response against them, preventing harmful reactions against the body's own tissues. This process is essential for maintaining homeostasis and preventing autoimmune diseases, as it allows the immune system to distinguish between self and non-self while responding appropriately to foreign antigens.
Xenograft: A xenograft is a tissue or organ transplant that is taken from one species and implanted into another species. This type of graft is significant in transplantation biology as it explores the possibilities of using animal organs to address human organ shortages. Xenografts can be used in research and clinical settings, but their use raises important questions about immune compatibility and rejection.