Immunopathology 2


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Immunopathology 2

  1. 1. Transplant Rejection
  2. 2. Transplantation of Solid Organs :Mechanisms Involved in Rejection : The antigens responsible for rejection in humans are those coded by genes of HLA ( Human Leukocyte Antigen ) system [ also known as MHC ( Major Histocompatibility Complex ) ] which are present on short arm of chromosome 6 . HLA genes are highly polymorphic.
  3. 3.  Any two individuals (other than identical twins) will express some HLA proteins that are different (allogeneic) . Thus, the recipient recognize them as foreign and attack them. Rejection is a complex process in which both cell-mediated immunity and circulating antibodies ( Humoral immunity ) play a role.
  4. 4. T Cell-Mediated Reactions:called cellular rejection, induced by two pathways :Direct pathway: Mediated by CD8+ T cells (Cytotoxic T Lymphocyte -CTL ). Recipient CD8+ T cells recognize antigens of graft donor presented by donor antigen-presenting cells found in the graft. CD8+ T cells recognize class I MHC antigens. CD8+ T cells, then differentiated into mature CD8+ T cells dependent on release of cytokines such as IL-2 from CD4+T helper cells. Once mature CD8+ T cells are generated, they kill grafted tissue by mechanisms already discussed.
  5. 5. Indirect pathway : Mediated by CD4+ T lymphocytes( Helper T cell) . Recipient CD4+ T lymphocytes recognize antigens of graft donor after they are presented by recipients own antigen-presenting cells . CD4+ T cells recognize class II MHC antigens ,and the result is delayed hypersensitivity type of reaction. It is postulated that direct pathway is major pathway in acute cellular rejection, while indirect pathway in chronic rejection. However, this separation is not absolute.
  6. 6. Antibody-Mediated Reactions:called humoral rejection, and take two forms:Hyperacute rejection : occurs when preformed antidonor antibodies are present in circulation of recipient. rejection occurs immediately after transplantation the circulating antibodies deposit rapidly on vascular endothelium of grafted organ. Complement fixation occurs resulting in thrombosis of vessels in graft, and ischemic death of graft.
  7. 7. Acute humoral rejection: In recipients not previously sensitized to transplantation antigens, exposure to class I and class II HLA antigens of donor may evoke antibodies. The antibodies formed, cause injury by several mechanisms, including complement-dependent cytotoxicity, inflammation, and antibody-dependent cell-mediated cytotoxicity. The initial target of these antibodies is graft vasculature. Thus sometimes referred to rejection vasculitis.
  8. 8. Morphology of Rejection Reactions :Rejection reactions are classified as hyperacute, acute, andchronic. Hyperacute Rejection: occurs within minutes or hours after transplantation. hyperacutely rejecting kidney rapidly becomes cyanotic, mottled, and flaccid and may excrete few drops of bloody urine. There is a rapid accumulation of neutrophils within arterioles, glomeruli, and peritubular capillaries. Subsequently, these changes become diffuse and intense, the glomeruli undergo thrombotic occlusion of capillaries, and fibrinoid necrosis occurs in arterial walls.
  9. 9. Acute Rejection: This may occur within days of transplantation in untreated recipient , or may appear months or even years later after immunosuppression has been terminated. acute graft rejection is a combined process in which both cellular and humoral tissue injuries contribute. Histologically, humoral rejection is associated with vasculitis, whereas cellular rejection is marked by interstitial mononuclear cell infiltrate.
  10. 10. Chronic Rejection: In recent years, acute rejection has been significantly controlled by immunosuppressive therapy, and chronic rejection has become an important cause of graft failure. Patients with chronic rejection present clinically with progressive rise in serum creatinine over a period of 4 to 6 months. Chronic rejection is dominated by vascular changes, interstitial fibrosis, and tubular atrophy with loss of renal parenchyma . The vascular changes consist of dense, obliterative intimal fibrosis, principally in renal cortical arteries.
  11. 11. Transplantation of Hematopoietic Cells : Use of hematopoietic cell transplants for: hematologic malignancies; certain nonhematologic cancers; aplastic anemias; and certain immunodeficiency states. Hematopoietic stem cells are usually obtained from bone marrow , but may also be harvested from peripheral blood after they are mobilized from bone marrow by administration of hematopoietic growth factors.
  12. 12.  In most conditions in which bone marrow transplantation is indicated, the recipient is irradiated with lethal doses or receive chemotherapy either to destroy the malignant cells (e.g., leukemias) ; or to create a graft bed (e.g., aplastic anemias). Three major problems arise in bone marrow transplantation:Graft-versus-host (GVH) diseaseTransplant rejectionImmunodeficiency
  13. 13. GVH disease: occurs in any situation in which immunologically competent cells or their precursors of donor are transplanted into immunologically crippled recipients. the transferred cells recognize alloantigens in the recipients . GVH disease occurs most commonly in setting of allogeneic bone marrow transplantation; but may also follow transplantation of solid organs rich in lymphoid cells (e.g., liver) .
  14. 14.  Recipients of bone marrow transplants are immunodeficient because of either their primary disease or prior treatment of disease with drugs or irradiation. When such recipients receive normal bone marrow cells from allogeneic donors, the immunocompetent T- cells present in donor marrow recognize recipients HLA antigens as foreign and react against them. Both CD4+ and CD8+ T cells recognize and attack the recipients tissues.
  15. 15. Acute GVH disease: occurs within days to weeks after allogeneic bone marrow transplantation. Although any organ may be affected, the major clinical manifestations result from involvement of epithelia of skin, liver, and intestines. Involvement of skin in GVH disease is manifested by a generalized rash. Destruction of small bile ducts gives rise to jaundice. Mucosal ulceration of the gut results in bloody diarrhea.
  16. 16. Chronic GVH disease: may follow the acute syndrome or may occur insidiously. These patients have extensive cutaneous injury, with destruction of skin appendages and fibrosis of dermis. The changes may resemble systemic sclerosis . Chronic liver disease manifested by cholestatic jaundice . Damage to gastrointestinal mucosa may cause esophageal strictures.
  17. 17. Transplant rejection: The mechanisms responsible for rejection of allogeneic bone marrow transplants are poorly understood. It seems to be mediated by NK cells and T cells that survive in the irradiated recipient.Immunodeficiency: Is a frequent accompaniment of GVH disease. Affected individuals are profoundly immunosuppressed and are easily infected. Although many organisms may infect patients, infection with cytomegalovirus is particularly important. Cytomegalovirus-induced pneumonitis can be fatal .
  18. 18. THANK YOU