Transplantation and Allograft Rejection

Barriers to transplantation

Allo-Antibodies – Hyperacute Rejection: pre-formed Abs against a foreign epitope in graft Þ complement response Þ immune attack. To avoid this Allo-Ab cross-matching is currently done before transplant.

T-cell mediated – T-cells’ normal function: recognize self MHC molecules + ‘foreign’ peptides.

Direct Allo-reactivity – Most common form of T-cell mediated rejection. T-cells from recipient directly recognize donor MHC molecules complexed with peptides derived from the donor. It probably happens because most MHC molecules have the same general structure. The polymorphisms from one MHC to another are found in the variable region where they bind Ag and not in the basic structure of the MHC. Directly reactivity leads to Acute Cellular Rejection.

Indirect Allo-reactivity – Recipient antigen presenting cells present donor peptide antigens to recipient T-cells. Analogous to what happens with a viral infection. This is probably the problem leading to chronic rejection. Paradoxically less common than direct reactivity.

Minor transplantation Ags – A transplant between people (ex: siblings) who have identical MHC alleles can be rejected due to subtle differences in the peptides which these MHC molecules present (minor antigens). Ex: inbred mice have same MHC, but an organ from a female mouse will be rejected by a male mouse because the male mouse has ‘male-specific antigens’. Minor antigens may be important for rejection of solid organ and in bone marrow transplantation.

Effector mechanisms of graft rejection

Direct cytotoxicity

Release of proinflammatory cytokines and chemoattractants by infiltrating T cells, macrophages and NK cells (Interferon gamma, tumor necrosis factor, nitric oxide, chemokines)

Induction of delayed type hypersensitivity responses in the graft

complement activation

Antibody dependent cytotoxicity

Nonimmune issues (ischemia, hypertension, drug induced toxicity)

Forms of Allograft rejection

(1) Hyper-acute Rejection – minutes to hours. From preformed donor specific antibodies or ABO incompatibilities. Bind to vascular endothelium and induce intrarenal intravascular coagulation. Results in immediate and irreversible graft loss. Prevention by crossmatching.

(2) Vascular Rejection – days. Manifests as Ý plasma creatinine. Accelerated humoral form (pre-formed Abs below level of detection by crossmatching). Enothelial cell inflammation, platelet and fibrin thrombi, necrosis and hemorrhage. Anti rejection treatment may help in 1/3 of patients, others lose graft.

(3) Acute Cellular Rejection – weeks-months. Manifests as Ý plasma creatinine. T cell mediated inflammation with specificity towards donor HLA antigens. Focal areas of tubulitis and or arteritis are often present

Approximately 90% respond to aggressive anti rejection therapy.

(4) Chronic Rejection – Months-years. Gradual rise in creatinine. HTN. Proteinuria. Chronic immune response. Kidney biopsy: concentric endothelial hyperplasia in blood vesselsÞ HTN. Tubules look atrophic and have fibrotic collagenous scar. There is no therapy for this.

Molecular events in T-cell activation

(1) T-cell receptor binds MHC/peptide complex on antigen presenting cell (APC).

(2) CD-28 on T-cell binds B7 (aka CD-80) on APC.

(3) CD-40L on T-cell binds CD-40 on APC.

Note: All of the above MUST happen to activate the T-cell. Blocking these interactions may block rejection (see below).

Treatment of graft rejection

Glucocorticoids – trap lymphoid cells in bone marrow, alter cytokines produced by the T cells to a less inflammatory phenotype, inhibit release and function of cytokines, inhibit transcription of inflammatory mediators produced by T cells, used in high doses for treatment of acute rejection.

Azathioprine – purine antagonist. inhibits DNA and RNA synthesis.

Mycophenolate Mofetil (MMF) – blocks de novo purine synthesis.

Cyclosporine A – binds to an intracellular immunophilin receptor called cyclophilin. This complex (cyclosporin:cyclophilin) binds to and inhibits the phosphatase activity of a protein called calcineurin, which is important for transcription of IL-2. This prevents proliferation of T cells.

Tacrolimus (FK506) – binds FK binding protein with analogous effects of cyclosporine (blocking of calcineurin).

Rapamycin – Macrolide antibiotic. Seems to bind to FK binding protein without affecting calcineurin, turns off T-cells and induces them to apoptosis.

OKT3 – anti-CD3 Ab which eliminates T-cells. Has significant side effects.

Immunologic Tolerance: The future of rejection treatment

CTLA-4 Ig - immunoglobulin like molecule which blocks CD28/B7 interaction

a CD40 - blocks CD40L and CD40 interaction.

NOTE: have to give these during time period of transplant; that way, only the T-cells responding to the transplant will be affected and not T-cells recognizing/responding to other things.