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The sequence of immunosuppressive drug administration determines composite tissue allograft survival
Solari MG, Washington KM, Zhang D, Jindal R, Unadkat JV, Pulikkottil BJ, Afrooz PN, Zheng XX, Thomson AW, Lee WP.
University of Pittsburgh
2010-04-05
Presenter: Mario G. Solari MD
Affidavit:
Director Name:
Author Category: Resident/Fellow
Presentation Category: Basic Science Research
Abstract Category: General Reconstruction
Background: Conventional multi-drug regimens are designed to suppress the immune system in order to prevent rejection. Calcineurin inhibitors such as cyclosporine (CsA) block the expansion of effector T cells (Teff), but also impair the development and function of T regulatory cells (Treg) . Rapamycin (RAPA), an mTOR inhibitor, has been shown to promote Treg in CTA. We report that the sequence of drug administration is critical to durable CTA tolerance.
Methods: Wistar-Furth to Lewis (full-MHC-mismatch) hindlimb transplants were performed in all groups. All groups received lymphocyte depletion with ALS followed by 21 days of drug therapy. Groups include CsA or RAPA alone, CsA + RAPA, and CsA followed by RAPA. Long-term surviving animals were challenged with skin grafts. In vitro studies include cytokine assays, FACS, PCR, and suppression assays.
Results: Both CsA and RAPA short-term monotherapy cannot prevent CTA rejection. Similar results are seen when both drugs are given simultaneously. However, when RAPA follows CsA (same short-term duration) 100% (n=7) demonstrate long-term survival (>500 days) and accept donor skin grafts and reject 3rd party. CsA inhibits Teff initially while RAPA increases Treg ratio in blood and lymphoid tissue. These Treg produce high levels of IL10 (a marker of tolerance) when stimulated in MLR and high levels of IL10 were measured in the serum of long-term surviving animals. The Treg from these animals suppress Teff in vitro.
Conclusion: Immunomodulatory regimens can be designed to balance acute rejection prevention and the promotion of regulatory mechanisms thereby minimizing the sequellae of immunosuppression such as infection and malignancy.
