Transplantation Immunopathology Lecture 15

Transplantation Immunopathology

• Solid organ and bone marrow transplants have become routine due to understanding of humoral and cellular immune response, development of immunosuppressive drugs, and understanding of MHC (Major Histocompatibility Complex) antigens.
• MHC antigens are cell surface antigens that determine whether transplanted tissue is recognized as foreign or not.

Types of Transplantation

• Allogeneic: Donor and recipient are related or unrelated but share similar HLA types.
• Syngeneic: Donor and recipient are identical twins.
• Autologous: Donor and recipient are the same person.

Immune Recognition of Allografts

• Rejection of allografts is a response to MHC molecules, which are highly polymorphic.
• There are two main mechanisms of host immune system recognition and response to MHC molecules on the graft:
  • Direct recognition: Host T cells directly recognize foreign MHC molecules on graft cells.
  • Indirect recognition: Host CD4+ T cells recognize donor MHC molecules after they are picked up, processed, and presented by host APCs.

Host-Versus-Graft Disease (HVGD)

• If the transplanted graft bears foreign MHC antigens, the recipient's immune system attacks the donor cells of the transplanted organ.
• Rejection involves T cell-mediated and circulating antibody responses.
• Three basic patterns of transplant rejection:
  • Hyperacute reaction: Occurs immediately after transplantation, often in kidney transplants.
  • Acute rejection: Usually occurs within the first few months after transplantation, evidenced by signs of organ failure.
  • Chronic HVGD: Occurs over a prolonged period, manifest by dense fibrosis of the intimal layer of blood vessels in the transplanted organ.

Graft-Versus-Host Disease (GVHD)

• GVHD occurs when the cellular immune system of the transplanted graft (donor T cells) recognizes and attacks the unrelated recipient HLA.
• Occurs mainly in:
  • Bone marrow transplant.
  • Severely immunocompromised patients who have received blood products containing HLA-incompatible lymphocytes.
  • After transplantation of solid organs rich in lymphoid cells (e.g., the liver).

Autoimmune Disorders

• Caused by a breakdown in the ability of the immune system to differentiate between self and non-self antigens.
• Normally, there is a high degree of immunologic tolerance to self-antigens, which prevents the immune system from destroying the host.
• Autoimmune diseases can affect almost any cell or tissue in the body.
• Some autoimmune disorders are tissue-specific, while others affect multiple organs and systems.

Mechanisms of Antibody-Mediated Diseases

• Opsonization and phagocytosis: Circulating cells coated with autoantibodies are targeted for phagocytosis by neutrophils and macrophages.
• Inflammation: Antibodies bound to cellular or tissue antigens activate the complement system, recruiting neutrophils and monocytes, triggering inflammation in tissues.
• Antibody-mediated cellular dysfunction:
  • Antibodies can impair or dysregulate cellular function without causing cell injury or inflammation (e.g., myasthenia gravis).
  • Antibodies can stimulate cell function inappropriately (e.g., Graves' disease).

Immunologic Tolerance

• The ability of the immune system to differentiate self from non-self antigens by the presence of HLA antigens.
• Autoimmune diseases result from loss of immune tolerance.
• Central tolerance: Elimination of autoreactive T cells in the thymus and B cells in the bone marrow.
• Peripheral tolerance: Deletion or inactivation of autoreactive T cells or B cells that escaped elimination in the central lymphoid organs.
• Several mechanisms in peripheral tissues that silence autoreactive T cells:
  • Anergy: Functional inactivation of lymphocytes.
  • Suppression of the response of T lymphocytes by regulatory T cells.
  • Activation-induced cell death: Apoptosis of mature lymphocytes as a result of self-antigen recognition.
  • Antigen sequestration: Some antigens are hidden from the immune system because they are located in immune-privileged sites.

Mechanisms of Autoimmune Disease

• Breakdown of self-tolerance and development of autoimmunity are related to the inheritance of various susceptibility genes and changes in tissues, often induced by infections or injury.
• Genetic factors play an important role in the development of autoimmune diseases.
• Role of infections and tissue injury:
  • Molecular mimicry: Viruses and other microbes share cross-reacting epitopes with self-antigens, leading to an immune response that attacks self-tissues.
  • Viral replication: Provirus genome integrates into host cell DNA, and viral gene expression is triggered by stimuli that activate infected cells.