Transplant Immunology

2. Mechanism of Action of Immunosuppressive Agents

Total Lymphocytes

4. Polyclonal Antibodies

5. Cyclosporine

7. Azathioprine

8. Mycophenolate Mofetil (RS-61443)

9. Corticosteroids (Prednisone, hydrocortisone, methylprednisolone)

10. Immunosuppression: Early Rejection Prophylaxis

11. Maintenance Immunosuppression Goal

13. TREATMENT OF REJECTION

Immunosuppression Flow-chart

14. Other options

Major Histocompatability Complex (MHC)-prime physiologic role is to recognize “self” from “nonself”; in humans, this is known as the HLA system

HLA: class I—HLA-A, B, C; expressed on all cells of an organism. Class I molecules present antigenic peptides to activated T lymphocytes expressing CD8 phenotype

class II—DP, DQ, DR; expressed on antigen presenting cells, e.g., B cells, T cells, macrophages, dendritic cells, and endothelium. Present to T lymphocytes expressing the CD4 phenotype.

-Pivotal cells moderating rejection are the T cells expressing the CD4 complex. These T cells recognize foreign Class II antigens on antigen presenting cells (APCs)—these cells not only present, but also provide signals (lymphokines/adhesion molecules) for T cell activation (second signal). There are two pathways for this to occur—direct and indirect routes of sensitization

-Activated CD4 cells are divided into Th1and Th2 populations: Th1 subpopulation produces: IL-2 (CD8 differentiation), INF (MHC class II differentiation), TNF (NO radicals/O2/Prostaglandins) Th2: IL-4,5,10—augments B cell mediated responses

-CD8 activation is thought to involve recognition of class I antigen (first signal) in a setting of increased levels of IL-2 (second signal) secreted by activated CD4 cells. Graft destruction ensues.

-Hyperacute rejection is secondary to pre-exisiting blood group antibodies, anti-MHC antibodies, or natural antibodies which react with the endothelial antigens—complement, coagulation, and kallikrein/bradykinin cascades activated. Leads to graft edema, hemorrhage, and vascular thrombosis.

-Accelerated rejection from IgM/IgG antibodies formed in response to the donor graft. Biopsy shows vascular destruction with a paucity of cellular infiltrate.

1. Cyclosporin (CyA) and FK506—inhibit lymphocyte proliferation and lymphokine production by binding to cytosolic intracellular receptors known as immunophilins (CyA-cyclophilins/FK506-FK506 proteins). These complexes inhibit calcineurin an intracellular protein phosphatase which plays a crucial role in the induction of lymphokine genes (IL-2). Side effects: renal dysfunction, GI, CNS, hypertension, and diabetes

2. Corticosteroids—negatively affecting the release of IL-1 and IL-6 from macrophages and thereby inhibiting IL-2 release. Side effects include hypertension, diabetes, cushingoid features, poor wound healing and asceptic bone necrosis

3. Azathioprine works non specifically by virtue of its antimetabolite effects to inhibit lymphocyte proliferation

4. OKT3—mouse monoclonal antibody against T cell receptor CD3 which nonspecifically suppresses all T cell functions. Use is generally in acute rejection episodes. Side effects: cytokine release causing fever, chills, and pulmonary edema; antibody production against the maurine antibody which precludes future courses; dramatic increase in lymphoproliferative disorders.

5. Rapamycin—homolog of FK506, but does not inhibit calcineurin. Mode of action is unclear. Has prevented development of cardiac allograft vasculopathy in rat allografts

6. 15-Deoxyspergualin (DSG)—binds cytoplasmic protein Hsc70 and interferes with antigen presentation and T and B cell development. Good for pancreatic islet cell survival. Causes myelosuppression

7. Mycophenolate mofetiln—inhibits inosine monophosphate dehydrogenase which blocks the de novo pathway for purine synthesis. This pathway is crucial for the proliferative response of T and B cell response. There is a low side effect profile.

8. Brequinar inhibits dihydrooratate dehydrogenase and blocks the de novo synthesis of pyrimidines. The proliferative response is attenuated.

-refers to the elimination of the immune response to the antigens of the transplant while the immune response to all other antigens remains intact

Anergy—inactivation of cells reactive to the foreign antigen; thought to be the result of T cells binding specific antigen, but not receiving the appropriate second signal from APCs or CD4 cells. IL-2 experimentally has been shown to reverse this

Clonal deletion—elimination of cells reactive to the foreign atigen; occurs primarily in the thymus by a process known as negative selection

Suppression—suppression of cells responsive to the foreign antigens by another, regulatory immulogic process. Veto cell—inhibits the activity of T cells reactive with antigens on its surface thereby suppressing the activity of the attacking cells