Immunosuppression is crucial for transplant success. It prevents rejection by suppressing the recipient's immune response against donor tissue. However, it's a delicate balance between protecting the graft and maintaining defense against infections and malignancies.

Various drug classes are used, including calcineurin inhibitors, antiproliferative agents, and corticosteroids. Each targets different aspects of the immune response. Careful monitoring and personalized regimens help manage the benefits and risks of immunosuppression.

Immunosuppression Fundamentals

Rationale for immunosuppressive therapy

• Prevent graft rejection by suppressing recipient's immune response against donor tissue and maintaining graft function and survival
• Address various types of rejection including hyperacute rejection (immediate), acute rejection (within weeks to months), and chronic rejection (long-term)
• Balance immunosuppression and immune function to prevent rejection while maintaining defense against infections (opportunistic pathogens) and malignancies (post-transplant lymphoproliferative disorder)

Classes of immunosuppressive drugs

• Calcineurin inhibitors (Tacrolimus, Cyclosporine) inhibit T cell activation and proliferation by blocking interleukin-2 production
• Antiproliferative agents (Mycophenolate mofetil, Azathioprine) inhibit lymphocyte proliferation by interfering with DNA synthesis
• Corticosteroids (Prednisone) exert broad anti-inflammatory and immunosuppressive effects through multiple mechanisms
• mTOR inhibitors (Sirolimus, Everolimus) inhibit T cell proliferation and differentiation by blocking cell cycle progression
• Biologics (Anti-thymocyte globulin, Alemtuzumab) deplete specific immune cell populations such as T cells or B cells

Immunosuppression Management

Benefits vs risks of immunosuppression

• Benefits include improved graft survival rates, reduced incidence of acute rejection, and potential for lower doses of individual drugs in combination regimens
• Risks encompass increased susceptibility to infections (cytomegalovirus, Pneumocystis jirovecii), higher risk of malignancies (skin cancers, lymphomas), and drug-specific side effects
• Drug-specific side effects include nephrotoxicity (calcineurin inhibitors), metabolic disorders (corticosteroids), and bone marrow suppression (antiproliferative agents)
• Drug interactions can affect immunosuppressant levels (grapefruit juice with calcineurin inhibitors)
• Development of donor-specific antibodies may lead to chronic rejection

Monitoring of immunosuppressive therapy

• Therapeutic drug monitoring measures drug levels in blood (trough levels for tacrolimus) and adjusts dosages to maintain therapeutic range
• Clinical monitoring involves regular follow-up appointments and laboratory tests to assess organ function (creatinine clearance for kidney transplants)
• Biomarkers for rejection include serum creatinine for kidney transplants and liver enzymes (ALT, AST) for liver transplants
• Adverse effect monitoring requires regular screening for infections (CMV PCR) and malignancies (skin examinations)
• Personalized immunosuppression tailors regimens based on individual risk factors, considering patient age, comorbidities, and immunological risk (panel reactive antibodies)

Strategies for transplant tolerance

• Mixed chimerism induces donor and recipient hematopoietic cell coexistence through bone marrow transplantation
• Regulatory T cell therapy expands and infuses recipient's regulatory T cells to promote immune tolerance
• Costimulation blockade targets T cell activation pathways (CD28/B7, CD40/CD40L) to induce anergy
• Mesenchymal stem cell therapy utilizes immunomodulatory properties of MSCs to suppress alloimmune responses
• Organ-specific strategies include liver transplant tolerance protocols exploiting the liver's unique immunological properties
• Bioengineered organs aim to reduce immunogenicity through tissue engineering techniques (decellularization/recellularization)
• Xenotransplantation advancements involve genetic modification of donor animals (pigs) to reduce immune response (α-1,3-galactosyltransferase knockout)