🛡️Immunobiology Unit 14 – Transplantation Immunology

Key Concepts in Transplantation

• Transplantation involves transferring cells, tissues, or organs (grafts) from a donor to a recipient to replace damaged or failing organs
• Autografts are transplants from one part of the body to another in the same individual (skin grafts)
• Allografts are transplants between genetically non-identical individuals of the same species (kidney transplants)
• Xenografts are transplants between different species (porcine heart valves)
• Major histocompatibility complex (MHC) plays a crucial role in graft rejection
  • In humans, MHC is known as the human leukocyte antigen (HLA) system
• Graft rejection occurs when the recipient's immune system recognizes the transplanted tissue as foreign and mounts an immune response against it
• Immunosuppressive drugs are used to prevent or minimize graft rejection by suppressing the recipient's immune response

Types of Transplants

• Solid organ transplants involve the transplantation of whole organs (heart, liver, kidney)
• Tissue transplants involve the transfer of specific tissues (skin, cornea, bone marrow)
• Hematopoietic stem cell transplants (HSCT) involve the infusion of stem cells to reconstitute the recipient's blood and immune system
  • Can be autologous (from the patient) or allogeneic (from a donor)
• Vascularized composite allotransplantation (VCA) involves the transplantation of multiple tissue types as a functional unit (hand, face)
• Islet cell transplantation involves the transfer of insulin-producing cells from the pancreas to treat type 1 diabetes
• Embryonic stem cell transplantation is a potential future therapy for regenerative medicine
• Xenotransplantation, while promising, faces significant immunological and ethical challenges

Immunological Basis of Rejection

• Graft rejection is primarily mediated by T cells that recognize foreign HLA molecules on the graft
• Direct allorecognition occurs when recipient T cells directly interact with donor antigen-presenting cells (APCs) expressing foreign HLA molecules
• Indirect allorecognition involves recipient APCs processing and presenting donor HLA peptides to recipient T cells
• CD8+ cytotoxic T lymphocytes (CTLs) directly kill graft cells expressing foreign HLA class I molecules
• CD4+ helper T cells secrete cytokines that promote inflammation and activate other immune cells
• B cells produce anti-HLA antibodies that can cause antibody-mediated rejection
• Natural killer (NK) cells contribute to graft rejection by recognizing missing self HLA class I molecules on the graft

HLA Matching and Compatibility

• HLA typing is performed to assess the compatibility between donor and recipient
• HLA genes are highly polymorphic, with numerous alleles at each locus
• HLA-A, HLA-B, and HLA-DR are the most important loci for graft rejection
• A six-antigen match (two alleles each at HLA-A, HLA-B, and HLA-DR) is considered the best match
• Haplotype matching takes into account the inheritance of HLA alleles on the same chromosome
• Cross-matching assesses the presence of preformed anti-HLA antibodies in the recipient against the donor
  • A positive cross-match indicates a high risk of antibody-mediated rejection
• HLA matching is more critical for some organs (kidney) than others (liver)
• Advances in immunosuppression have allowed for successful transplantation despite HLA mismatches

Mechanisms of Graft Rejection

• Hyperacute rejection occurs within minutes to hours after transplantation due to preformed anti-HLA antibodies
  • Characterized by rapid graft failure and thrombosis
• Acute rejection typically occurs within days to weeks after transplantation
  • Mediated by T cells and antibodies
  • Characterized by infiltration of immune cells and graft dysfunction
• Chronic rejection develops months to years after transplantation
  • Characterized by gradual graft deterioration and fibrosis
  • Mediated by both cellular and humoral mechanisms
• Graft-versus-host disease (GVHD) can occur in HSCT when donor T cells attack recipient tissues
• Ischemia-reperfusion injury during transplantation can enhance graft immunogenicity and promote rejection

Immunosuppressive Therapies

• Immunosuppressive drugs are used to prevent or treat graft rejection
• Induction therapy is administered at the time of transplantation to prevent acute rejection
  • Includes antibodies against T cells (anti-thymocyte globulin) or IL-2 receptor (basiliximab)
• Maintenance therapy is used long-term to prevent chronic rejection
  • Calcineurin inhibitors (cyclosporine, tacrolimus) inhibit T cell activation
  • Antiproliferative agents (mycophenolate mofetil, azathioprine) inhibit lymphocyte proliferation
  • mTOR inhibitors (sirolimus, everolimus) block T cell proliferation and differentiation
  • Corticosteroids have broad anti-inflammatory and immunosuppressive effects
• Targeted therapies aim to specifically modulate the immune response
  • Costimulation blockade (belatacept) inhibits T cell activation
  • Proteasome inhibitors (bortezomib) target plasma cells producing anti-HLA antibodies
• Immunosuppression must be carefully balanced to prevent rejection while minimizing side effects and opportunistic infections

Complications and Challenges

• Immunosuppressive drugs have significant side effects
  • Increased risk of infections (cytomegalovirus, pneumocystis pneumonia)
  • Malignancies (post-transplant lymphoproliferative disorder)
  • Nephrotoxicity and hypertension with calcineurin inhibitors
  • Diabetes and osteoporosis with corticosteroids
• Chronic rejection remains a major cause of long-term graft failure
• Antibody-mediated rejection is difficult to treat and often requires intensive immunosuppression
• Non-adherence to immunosuppressive medications can lead to graft rejection
• Organ shortage is a significant challenge, with many patients on waiting lists
• Ethical considerations surrounding organ allocation and living donation
• Financial burden of transplantation and lifelong immunosuppression

Future Directions in Transplantation

• Developing more targeted and less toxic immunosuppressive therapies
  • T cell costimulation blockade
  • Regulatory T cell therapy
  • Chimeric antigen receptor (CAR) T cells
• Inducing tolerance to minimize or eliminate the need for long-term immunosuppression
  • Mixed chimerism through HSCT
  • Thymic manipulation to promote central tolerance
• Expanding the donor pool through organ preservation and optimization
  • Ex vivo perfusion systems
  • Organ regeneration and bioengineering
• Xenotransplantation as a potential solution to organ shortage
  • Genetically modified pigs as a source of organs
  • Overcoming immunological and physiological barriers
• Personalized medicine approaches to optimize immunosuppression and predict rejection risk
  • Pharmacogenomics to guide drug selection and dosing
  • Biomarkers to monitor graft function and immune status
• Addressing disparities in access to transplantation and improving long-term outcomes