Immunosuppression

History of Immunosuppression

Mythic literature richly describes transplantation as a cure for disease, although the clinical practice of transplantation spans relatively few decades. The necessity for pharmacologic treatment to facilitate transplantation was first described in the fifth century BC. Advances in the practice of this life-enhancing technology are integrally related to developments in the field of immunosuppression. From 1910 to 1960, radiation (total-body or total lymphoid) and nonselective chemical reagents (benzene and toluene) were employed to destroy rapidly dividing cells in a nonselective fashion.

The introduction of the antiproliferative drug 6-mercaptopurine (6-MP) initiated the modern era of pharmacologic immunosuppression. The nitroimidazole derivative of 6-MP, azathioprine (Aza), improved the oral bioavailability of 6-MP. Corticosteroids were then added to the Aza immunosuppressive regimen on an empiric basis.

The major advance in immunosuppression in the past three decades has been the development of pharmacologic agents that inhibit T cells relatively selectively, the prototype of which is cyclosporine (CsA). The timeline of the development of immunosuppressive agents reflects a progression from the use of agents that act in a nonselective fashion on functions common to a variety of tissues (steroids, nucleoside synthesis inhibitors, alkylating agents) to the use of immunosuppressants that focus their actions selectively on T and/or B cells by inhibiting lymphokine generation (CsA, tacrolimus), signal transduction (sirolimus, leflunomide), or differentiation (15-deoxyspergualin) pathways.

Unfortunately the microbial products presently available to inhibit T cell processes display a degree of nonspecificity that leads to pleiotropic renal, neural and hepatic toxicities, and intrinsic therapeutic inconsistencies that produce a broad range of both pharmacokinetic and pharmacodynamic interindividual variations. Because of these limitations of individual agents, present strategies seek to use synergistic drug combinations to potentiate rejection prophylaxis, and more importantly to permit individual drug dose reduction to broaden the therapeutic window. The coming millennium should witness the development of immunological tolerance approaches based upon donor antigen presentation as peptide or protein moieties, and/or immunomodulation by highly selective monoclonal antibodies or cell infusions to achieve freedom from ongoing immunosuppressive therapy, with its consequent hazards of neoplasia, infection, and rejection due to physician/patient noncompliance.

Cyclosporine (Neoral) view mechanism of action

Reducing the Rate of Chronic Rejection

Neoral, a new formulation of cyclosporine (CsA), is more rapidly and completely absorbed than either the conventional olive oil liquid or gelcap formulation of CsA.

While monitoring the levels of CsA in patients' blood, Dr. Barry Kahan and Senior Research Nurses Maria Welsh and Linda Schoenberg noticed a pattern. It seemed that the patients whose CsA concentrations varied were the ones most prone to chronic rejection and/or graft loss.

We formulated the hypothesis that patients with high variability of CsA concentrations had high rates of rejection and graft loss, and reasoned that without consistent amounts of CsA, a patient's immune system is more likely to reject a graft. Perhaps if CsA was absorbed into a patient's body at a consistent level, that patient might have a better chance of accepting a graft.

Since its introduction to the immunosuppressive armamentarium almost two decades ago, cyclosporine (CsA; Sandimmune, Sandoz Pharma Ltd., SZ), a cyclic endecapeptide extracted from Tolypocladium inflatum Gams, has become the cornerstone of maintenance immunosuppression. However, the wide array of toxic side effects of CsA has led us to define clinically relevant pharmacological strategies that broaden its narrow therapeutic index. One strategy to reduce the incidence of allograft rejection is to combine CsA with an agent(s) that acts synergistically in order to allow CsA dose reduction and mitigation of drug-induced toxicity.

Sirolimus (Rapamycin)

Our studies in rodents suggest that a combination of immunosuppressive agents that act during two sequential phases of the cell cycle, namely the G₀ to G₁ transformation (CsA) and the G1 build-up (sirolimus, SRL; rapamycin; Rapamune, Wyeth, US), display a greater degree of immunosuppressive synergism than two agents that both act on the G₀ to G₁ transformation (CsA and anti-T cell receptor (TcR) monoclonal antibodies [MAb]), or two agents that interrupt the nonsequential G₀ to G₁ and S phases of the cell cycle (CsA and brequinar [BQR; DuP785, DuPont-Merck, US]).

The synergistic interaction between SRL and CsA may be related to their sequential molecular mechanisms of action. CsA inhibits the Ca2+-dependent processes of lymphokine synthesis by T cells during the G₀ to G₁ transition of the cell cycle. SRL blocks Ca2+-independent events during the G₁ phase, including transduction of the second signals delivered by interleukin-2 (IL-2), IL-4, or IL-6.

Assessment of the nature of drug interactions demands strict measurement of dose-effect relationships for each drug alone and in combination. Chou used the mass action law to express a theoretical model and derive the median effect equation and the combination index (CI), a parameter of drug interaction that has proven applicable in studies of HIV and cancer chemotherapy. Interactions are considered additive if CI values equal 1.0, synergistic if they equal less than 1.0, and antagonistic if they are greater than 1.0.

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