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The addition of IL-2 immunomodulation to FK506 therapy enhances long-term survival of hind-limb allotransplantation
Timothy W. Ng, BS, Dolores Raunicher-Wolfram, MD, Dong Zhang, MD, Ph.D., W.P. Andrew Lee, MD and Xin Xiao Zheng, MD.
2010-04-05
Presenter: Timothy W. Ng
Affidavit:
Director Name:
Author Category: Resident/Fellow
Presentation Category: Basic Science Research
Abstract Category: General Reconstruction
Purpose: Despite optimum immunosuppression in clinical hand transplantation, tolerance remains a distant possibility. Using immunomodulation rather than immunosuppression may provide the key to tolerance. Tregs require interleukin-2 (IL-2) for survival. Depletion strategy along with tacrolimus (FK506) is widely used in transplantation, but is not tolerogenic since FK506 blocks interleukin-2 (IL-2) transcription and consequent IL-2 dependent regulation. Therefore, we hypothesized that the addition of IL-2 combined with immune depletion and FK506 will induce immunomodulation and promote hind-limb allograft tolerance.
Hypothesis: Adding IL-2/Fc, a long-lasting form of IL-2, to anti-lymphocyte serum (ALS) and FK506 will enhance Treg survival and consequent long-term survival of CTA.
Methods: Orthotopic hind-limb transplantation from Brown-Norway to Lewis rats was performed. Groups as per [figure1]. End point: Survival to 250 days post transplant or skin and muscle necrosis. P<0.05 was considered significant on Logrank test.
Results: Mean survival in ALS, FK, FK+IL-2, ALS+FK and IL2+FK+ALS was 9.25+1.5, 33+2.65, 35.5+2.65, 117.5+86.18 and 237 days respectively. All animals IL2+ALS+FK except one, which died due to hemorrhage, had long-term allograft survival > 200 days (Figure 1). Logrank test for trend revealed a P-value < .0001.
Conclusions: Adding IL-2/Fc to ALS and FK506 therapy permits long-term CTA survival. Enhanced survival of T regulatory cells due to IL-2 may be the mechanism for this increased survival. Addition of IL2 to current clinically used strategy of depletion and CsA represents a potential for tolerance induction to CTA.
