High dose of antithrombin III induces indefinite survival of fully allogeneic cardiac grafts and generates regulatory cells.
ABSTRACT The authors investigated whether antithrombin III (AT-III) could induce unresponsiveness to alloantigens.
CBA mice were given intravenous injection of 50 or 500 U/kg AT-III or control plasma the same day as transplantation of a heart from a C57BL/6 mouse. An adoptive transfer study and mixed leukocyte culture analysis were also performed.
Naive CBA mice rejected C57BL/6 cardiac grafts acutely (median survival time [MST], 9 days). The 50-U/kg dose of AT-III induced a moderate increase in graft survival (MST, 25 days), whereas control mice rejected their graft acutely (MST, 7 days). With the 500-U/kg dose of AT-III, all grafts survived indefinitely (>100 days) and regulatory cells were generated. In vitro, AT-III suppressed proliferation of mixed leukocyte responses and generation of interleukin-2.
AT-III can be not only an antithrombotic agent but also a strong immunomodulating agent when used at high dose.
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ABSTRACT: 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. This study investigated the effect of an agonistic anti-BTLA mAb (3C10) in the fully major histocompatibility complex-mismatched murine cardiac transplantation. 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, anti-interleukin (IL)-2 receptor alpha antibody (PC-61) or anti-IL-10 antibody (JES-2A5) was administered to a 3C10-treated CBA recipient. CBA mice treated with one and four doses of 3C10 prolonged allograft survival (median survival times [MSTs], 43 and >100 days, respectively). Secondary CBA recipients given whole splenocytes or CD4 cells from primary 3C10-treated CBA recipients had significantly prolonged survival of C57BL/6 hearts (MSTs, >100 in both). Also, flow cytometry studies showed an increased CD4CD25Foxp3 cell population in 3C10-treated mice. Additionally, IL-2 and interferon-γ production were suppressed in 3C10-treated mice, and IL-4 and IL-10 from 3C10-treated CBA mice increased. Moreover, 3C10 directly suppressed alloproliferation in a mixed leukocyte culture. However, administration of PC-61 or JES-2A5 clearly attenuated prolonged survival of 3C10-treated mice (MSTs, 15.5 and 13.5 days, respectively). 3C10 could control acute rejection by its suppressive effect on alloreactive T cells and induction of IL-10-dependent regulatory CD4 T cells.Transplantation 01/2014; · 3.78 Impact Factor
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