Immunosuppression principles

Rejection Basics - Host vs. Graft

• Graft-vs-Host Disease (GVHD): Occurs when donor T-cells (from the graft) recognize the recipient's body (host) as foreign and mount an immune attack.
• Key Mediator: Donor T-lymphocytes, particularly cytotoxic T-cells, targeting host tissues.
• Common Manifestations (Triad):
  • Skin: Maculopapular rash
  • Liver: Jaundice, elevated liver enzymes
  • GI Tract: Diarrhea, abdominal pain, nausea

⭐ GVHD is most commonly associated with bone marrow/stem cell and liver transplants.

The Drug Arsenal - Taming the T-Cell

• Primary Goal: Inhibit T-cell activation, the central driver of acute rejection. This process requires three distinct signals.

• Calcineurin Inhibitors (CNIs): Tacrolimus & Cyclosporine.
  • Block Signal 1 by inhibiting calcineurin, preventing IL-2 production.
  • Toxicity: Nephrotoxicity, neurotoxicity (tremor), HTN, hyperglycemia.
• mTOR Inhibitors: Sirolimus & Everolimus.
  • Block Signal 3 by inhibiting mTOR, blocking IL-2-driven proliferation.
  • Toxicity: Pancytopenia, delayed wound healing, hyperlipidemia.
• Antimetabolites: Mycophenolate Mofetil (MMF) & Azathioprine.
  • Inhibit purine synthesis, starving proliferating lymphocytes.
  • Toxicity: MMF (GI distress), Azathioprine (myelosuppression).

⭐ CNI-induced nephrotoxicity is a major cause of chronic allograft dysfunction, causing afferent arteriole vasoconstriction and chronic fibrosis.

Toxicities & Side Effects - The Nasty Sidekicks

• Calcineurin Inhibitors (Tacrolimus, Cyclosporine):

  • Nephrotoxicity: Acute (afferent arteriole vasoconstriction) & chronic (fibrosis).
  • Neurotoxicity: Tremors, headache, seizures.
  • Metabolic: Hypertension, ↑ lipids, ↑ glucose (esp. Tacrolimus).
  • Cyclosporine-specific: Gingival hyperplasia, Hirsutism.

• Antiproliferatives:

  • Mycophenolate (MMF): GI distress (diarrhea), leukopenia.
  • Azathioprine: Dose-related myelosuppression (check TPMT), pancreatitis.

• mTOR Inhibitors (Sirolimus, Everolimus):

  • Pancytopenia, poor wound healing, mouth ulcers (stomatitis).
  • Hyperlipidemia/Hypertriglyceridemia.

• Corticosteroids (Prednisone):

  • Cushingoid features, osteoporosis, hyperglycemia, avascular necrosis, cataracts.

⭐ Calcineurin inhibitor nephrotoxicity is a major cause of long-term allograft dysfunction. It's primarily mediated by dose-dependent vasoconstriction of the afferent arterioles, leading to a ↓ GFR.

Clinical Regimens - The Balancing Act

• Induction Therapy (Peri-transplant): High-dose agents to prevent hyperacute/acute rejection.

  • Antibodies: Basiliximab (IL-2R blocker), Alemtuzumab, Antithymocyte Globulin.
  • High-dose corticosteroids.

• Maintenance Therapy (Lifelong): A multi-drug approach to prevent chronic rejection.

  • Cornerstone: Calcineurin Inhibitor (CNI) (e.g., Tacrolimus) + Antimetabolite (e.g., Mycophenolate Mofetil) ± Corticosteroids.

• Rejection Treatment: For acute episodes, typically pulse high-dose corticosteroids.

⭐ The primary challenge is balancing under-immunosuppression (risk of rejection) against over-immunosuppression, which leads to opportunistic infections (CMV, BK virus) and malignancy (PTLD, skin cancer).

High‑Yield Points - ⚡ Biggest Takeaways

• Calcineurin inhibitors (e.g., Tacrolimus) are the backbone of therapy but are highly nephrotoxic.
• Antimetabolites (e.g., Mycophenolate) inhibit lymphocyte proliferation, causing bone marrow suppression.
• mTOR inhibitors (e.g., Sirolimus) block T-cell signaling but classically impair wound healing.
• Corticosteroids are used for induction and managing acute rejection.
• Induction therapy with IL-2R antagonists (Basiliximab) prevents early acute rejection.
• Prophylaxis against PCP and CMV is a standard of care.