2011 - BSS 2011 Symposium
4.1 - Regulatory T cell therapy in mice and translation to man
Presenter: Qizhi, Tang, San Francisco, United States
Authors: Karim Lee1, Monika Laszkowska1, Vinh Nguyen1, Todd Brennan2, Sang-Mo Kang1, Qizhi Tang1
Regulatory T cell therapy in mice and translation to men
Karim Lee1, Monika Laszkowska1, Vinh Nguyen1, Todd Brennan2, Sang-Mo Kang1, Qizhi Tang1
1Department of Surgery, University of California, San Francisco, San Francisco, CA; 2Department of Surgery, Duke University Medical Center DUMC 3512, Durham, NC; USAAlthough Tregs are essential for peripheral tolerance, adoptive Treg therapy alone is insufficient to confer long-term allograft survival in lymphoreplete hosts without preconditioning or adjunct immunosuppression. We hypothesized that reducing donor-reactive T cells may create a therapeutic window for Tregs to induce allograft tolerance without additional immunosuppression. To test this hypothesis, we preconditioned recipient mice using donor-specific transfusion followed by cyclophosphamide treatment to selectively delete proliferating donor-reactive cells. This approach reduced donor-reactive T cells by 70-90%, but failed to prolong islet allograft survival in BALB/c to C57BL/6 mouse model of transplantation. Pre-transplant administration of Tregs with direct donor reactivity alone did not lead to prolongation of islet allograft survival. However, a combination of donor-specific depletion and donor-specific Tregs led to long-term survival of islet allograft in 70% of the recipients. Equal numbers of polyclonal Tregs significantly prolonged graft survival, but 90% of the recipients rejected their grafts by 100 days. Increasing the numbers of polyclonal Tregs five fold was able to confer long-term graft protection. In contrast, a similar strategy of combining donor-reactive T cell reduction and polyclonal Tregs did not protect allogeneic islets in autoimmune NOD recipients. Further addition of Tregs specific for islet autoantigen was required to prolong graft survival in NOD mice. These results demonstrate that donor-specific Tregs have superior efficacy than polyclonal Tregs. Therefore, we developed a robust protocol to expand human donor-specific Tregs for future testing of the safety and efficacy of Treg therapy in transplant patients. We achieved 50-300 fold expansion in 14 days using two rounds of stimulation with activated donor B cells. The expanded Tregs were virtually all donor-specific, expressed a CD4+Foxp3+CD27+CD62Lhi phenotype, and exhibited potent donor-specific suppression. We envision a clinical protocol that combines T cell ablative induction and donor-specific Treg infusion for promoting transplant tolerance in patients. Together, these results demonstrate a clinically viable approach to harness the tolerogenic property of Tregs for inducing long-term allograft acceptance.
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