High dose of antithrombin III induces indefinite survival of fully allogeneic cardiac grafts and generates regulatory cells

Abstract

AT-III can be not only an antithrombotic agent but also a strong immunomodulating agent when used at high dose.

Induction of Regulatory T Cells and Indefinite Survival of Fully Allogeneic Cardiac Grafts by Ursodeoxycholic Acid in Mice

“…We previously found that IL-10 was required for the induction and effector function of regulatory cells in another murine cardiac transplantation model (30). In addition, we and others have observed that agents with antiinflammatory and immunomodulatory activity are able to induce regulatory cells (18,20,21,(31)(32)(33). These findings and the results of our adoptive transfer studies indicate that treatment with UDCA may induce indefinite survival of allografts by means of generation of regulatory cells.…”

“…We previously reported that some anti-inflammatory or immunomodulatory agents induce unresponsiveness to fully allogeneic grafts by means of generation of regulatory cells (18,20,21). In the current investigation, we conducted adoptive transfer studies to determine whether generation of regulatory cells was involved in the induction of unresponsiveness by UDCA treatment.…”

Antigen-induced regulatory T cells

“…Other molecules not generally considered to be part of the immunologic repertoire may also contribute: for example, administration of high doses of antithrombin III (500 U/kg) led to indefinite survival of fully allogeneic murine cardiac grafts by inducing Trs. 80 It is possible that antithrombin III at these nonphysiologic doses has the properties of an as-yet-unidentified protease inhibitor that would normally perform this function.…”

Microvascular Thrombosis and Cardiac Allograft Vasculopathy in Rat Heart Transplantation

“…26 Treatment with antithrombin inhibited T-and B-lymphocyte activation and improved parameters of inflammation in a rat model of lung transplantation, 27,28 and induced indefinite survival of fully allogeneic cardiac grafts. 10,11 Interestingly, antithrombin can affect inflammatory processes via inhibition of nuclear factor-B, and these effects could directly inhibit expression of pro-inflammatory molecules and tissue factor, because these genes are known to be under the control of nuclear factor-B. 29 Treatment with hirudin in a rat model of cardiac transplantation inhibited tissue factor expression and decreased neo-intimal hyperplasia, suggesting that hirudin, in addition to the direct effects on thrombin inhibition, may attenuate the hypercoagulable state and prevent the development of CAV.…”

“…9 Second, administration of antithrombin induces indefinite survival of fully allogeneic grafts in a mouse model of cardiac transplantation, suggesting that administration of high-dose antithrombin may be useful as adjuvant therapy to the currently used immunosuppressive therapies after organ transplantation. 10,11 Previous findings in humans and in rodent models of heart transplantation led us to investigate: (a) whether a hypercoagulable microvasculature defined by the presence of microvascular fibrin deposits and capillary antithrombin binding could be identified in a rat model of heterotopic heart transplantation; and (b) whether the presence of a hypercoagulable microvasculature is associated with the development of CAV in a rat model. These investigations are relevant when we consider previous research demonstrating that the presence of a hypercoagulable microvasculature is directly associated with the development and progression of CAV and allograft failure in humans.…”