Background: The co-inhibitory receptor B and T lymphocyte attenuator (BTLA) has been implicated in the regulation of autoimmunity and may potentially play an important role in allograft tolerance. We investigated the effect of an agonistic anti-BTLA mAb (3C10) in the survival of fully MHC-mismatched murine heart transplantation.
Methods: CBA mice underwent transplantation of C57BL/6 hearts and received one dose of 3C10 on the day of transplantation (day 0) or four doses of 3C10 on day 0, 3, 6 and 9. Adoptive transfer studies were performed to determine whether regulatory cells were generated. Moreover, to confirm the requirement for regulatory T cell and Th-2 cytokines, we administrated anti-interleukin (IL)-2 receptor alpha antibody (PC-61) or anti-IL-10 antibody (JES-2A5) to 3C10-treated CBA mice. Also, histologic, immunohistochemistry, cell-proliferation, cytokine, flow cytometry assessments, and measurement of donor-specific antibody were performed.
Results: CBA mice treated with one and four doses of 3C10 significantly prolonged allograft survival (median survival times [MSTs], 43 and >100 days, respectively). Secondary CBA recipients given whole splenocytes or splenic CD4+ cells from primary 3C10-treated CBA recipients had prolonged survival of C57BL/6 hearts (MSTs, >100 in both). Flow cytometry studies showed an increased CD4+CD25+Foxp3+ cell population in 3C10-treated mice. However, prolonged survival of 3C10-treated mice was clearly attenuated by administration of PC-61 and JES-2A5 (MSTs, 15.5 and 13.5 days, respectively). Additionally, IL-2 and interferon (IFN)-Γ production were suppressed in 3C10-treated mice, and production of IL-4 and IL-10 from 3C10-treated transplant recipients increased compared to that from splenocytes of untreated recipients. Moreover, 3C10 directly suppressed allo-proliferation in a mixed leukocyte culture.
Conclusion: 3C10 could control acute rejection by its suppressive effect on alloreactive T cells and induction of IL-10 dependent regulatory CD4+ T cells.
To cite this abstract in AMA style:Uchiyama M, Jin X, Zhang Q, Yu L, Bashuda H, Matsuda H, Yagita H, Niimi M. Agonistic Anti-BTLA mAb (3C10) Induced Prolongation of Murine Cardiac Allograft and Generation of IL-10 Dependent Regulatory CD4+ T Cells, An [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/agonistic-anti-btla-mab-3c10-induced-prolongation-of-murine-cardiac-allograft-and-generation-of-il-10-dependent-regulatory-cd4-t-cells-an/. Accessed December 8, 2019.
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