4.3 Transplant Immunology & Immune Pharmacology

Allorecognition: Why Foreign Grafts Are Seen

Transplanted tissues express donor MHC (HLA) molecules loaded with peptides. Recipient T cells recognize foreign MHC directly on graft APCs (direct allorecognition) or process donor antigens presented on recipient APCs (indirect allorecognition). Because TCR repertoires are selected on self-MHC, many clones cross-react strongly with allogeneic MHC—explaining vigorous rejection without prior sensitization in some settings, and even stronger responses when memory exists.

HLA matching concept

HLA genes are highly polymorphic. Closer matching at key loci (especially HLA-A, -B, and -DR in many solid-organ and HSCT contexts) reduces the density of foreign epitopes that T cells attack, lowering rejection and GVHD risk. Perfect matching is not always available; immunosuppression compensates. ABO blood-group compatibility remains critical because preformed isohemagglutinins can destroy grafts—linking transfusion rules to hyperacute risk.

Rejection Timing and Mechanisms

Hyperacute is a Type II-like endothelial attack by preformed antibodies (prior transplant, pregnancy, transfusion). Acute cellular rejection is largely Type IV (CD4 help + CD8 killing of graft cells). Acute humoral rejection uses donor-specific antibodies with complement activation (C4d staining is a pathology marker of classical pathway activity on endothelium). Chronic rejection combines repeated immune injury with ischemia and drug toxicity, producing irreversible scarring.

Graft-versus-Host Disease (GVHD)

In allogeneic hematopoietic stem-cell transplantation, the graft contains mature donor T cells. If the host is immunocompromised and tissues express alloantigens the donor T cells recognize, those T cells attack host skin (rash), liver (jaundice, enzyme rise), and gut (diarrhea)—classic GVHD triad. Acute GVHD is largely alloreactive T-cell–driven; chronic GVHD has autoimmune-like fibrosis features. Host-versus-graft dominates solid-organ rejection; graft-versus-host dominates when the immune system itself is transplanted. Mild graft-versus-tumor effects can be beneficial in leukemia, illustrating the double edge of alloreactivity.

Immune Pharmacology: Mechanism First, Toxicity Linked

Immunosuppressants interrupt activation, IL-2 signaling, proliferation, or specific cytokines/cells. Learn where in the pathway each class acts, then the predictable adverse effects of that mechanism.

Calcineurin inhibitors (cyclosporine, tacrolimus)

TCR signaling raises calcium → calcineurin dephosphorylates NFAT → NFAT enters the nucleus and drives IL-2 (and other) transcription. Calcineurin inhibitors bind immunophilins (cyclosporine–cyclophilin; tacrolimus–FKBP) and block calcineurin, starving T-cell IL-2 production. Classic toxicities: nephrotoxicity, hypertension, neurotoxicity (tremor); cyclosporine is associated with gingival hyperplasia and hirsutism; tacrolimus with more glucose intolerance—details vary by source but nephrotoxicity is shared and high-yield.

mTOR inhibitors (sirolimus/rapamycin, everolimus)

IL-2 receptor signaling activates PI3K–Akt–mTOR, promoting cell-cycle progression and proliferation. mTOR inhibitors complex with FKBP and block mTOR, arresting lymphocytes in G1 even if IL-2 is present. They are often synergistic with calcineurin inhibitors but used carefully because of impaired wound healing, hyperlipidemia, and cytopenias/mouth ulcers—consistent with antiproliferative effects on nonimmune tissues.

Antimetabolites (azathioprine, mycophenolate mofetil)

Azathioprine is converted to 6-mercaptopurine metabolites that inhibit purine synthesis, impairing lymphocyte proliferation (lymphocytes depend on de novo purine pathways). TPMT deficiency increases myelotoxicity risk—classic pharmacogenetic pearl. Mycophenolate inhibits inosine monophosphate dehydrogenase (IMPDH), preferentially blocking guanosine synthesis in lymphocytes. Toxicities: myelosuppression, GI upset; infection risk from global lymphocyte impairment.

Glucocorticoids (prednisone and congeners)

Genomic effects: glucocorticoid receptor modulates transcription, broadly suppressing NF-κB–driven cytokines (IL-1, IL-6, TNF, etc.), reducing leukocyte trafficking, and inducing apoptosis of some lymphoid cells. Used for induction, rejection pulses, and autoimmunity. Toxicities reflect physiology of excess cortisol: hyperglycemia, osteoporosis, Cushingoid habitus, HPA suppression, infection risk, impaired wound healing, mood changes—not single-pathway specific but highly testable as class effects.

Biologics: anti-TNF and anti-CD20

Anti-TNF agents illustrate that TNF is essential for macrophage containment of mycobacteria—blocking it removes a checkpoint that keeps latent TB sequestered. Anti-CD20 shows that B cells contribute both antibody and antigen presentation; depletion helps antibody-mediated autoimmunity (e.g., some RA, vasculitis, pemphigus contexts) and certain lymphomas.

Other pathway notes (high-yield adjacency)

Basiliximab/daclizumab-type IL-2 receptor (CD25) antibodies block IL-2 growth signals on activated T cells (induction). Belatacept (CTLA-4–Ig family) blocks B7–CD28 costimulation, promoting anergy. ATG depletes T cells. These reinforce the same activation cascade: signal 1 (TCR–MHC), signal 2 (costimulation), signal 3 (cytokines/IL-2).

Integrated Clinical–Mechanism Cases

• Immediate graft thrombosis with positive crossmatch → hyperacute, preformed antibody/complement; no drug on earth reverses minutes-scale MAC/thrombosis—prevention is the lesson.
• Week-2 rising creatinine, lymphocytic tubulitis after living-donor kidney → acute T-cell rejection; escalate steroids/optimize calcineurin inhibitor.
• Years later, progressive fibrosis and concentric vascular thickening → chronic rejection.
• Post-HSCT rash + diarrhea + bilirubin rise → GVHD from donor T cells.
• RA patient on infliximab develops reactivation TB → anti-TNF removed granuloma integrity.
• Transplant patient on tacrolimus with rising creatinine → calcineurin-inhibitor nephrotoxicity versus rejection must be distinguished clinically, but mechanism of drug injury is afferent arteriolar vasoconstriction/toxicity from calcineurin blockade in the kidney.

Summary Table: Drug Class → Pathway Node

Master these nodes and the rejection timing table; most CBSE transplant/immunopharmacology items are recombinations of the same mechanism map rather than obscure drug trivia.