Redefining Peripheral Tolerance in the Balb/C to Cba Mouse Cardiac Allograft Model

The Journal of Immunology

Balin

Mashayekhi

et al. 2005

NF-κB is a key regulator of transcription after TCR and costimulatory receptor ligation. To determine the role of T cell-intrinsic NF-κB activation in acute allograft rejection, we used IκBαΔN-Tg mice (H-2b) that express an inhibitor of NF-κB restricted to the T cell compartment. We have previously shown that these mice permanently accept fully allogeneic (H-2d) cardiac grafts and secondary donor skin grafts, and that splenocytes from these tolerant mice have reduced alloreactivity when restimulated in vitro. These results were compatible with either deletion or suppression of allospecific T cells as possible mechanisms of tolerance. The aim of this study was to investigate the mechanism of transplant tolerance in these mice. IκBαΔN-Tg mice did not have increased numbers or function of CD4+CD25+ regulatory T cells either before or after cardiac transplantation. In addition, tolerance could not be transferred to fresh NF-κB-competent T cells and was not permissive for linked suppression to skin grafts sharing donor and third-party alloantigens, suggesting that dominant suppression is not the mechanism by which IκBαΔN-Tg mice achieve tolerance. In contrast, overexpression of the antiapoptotic protein Bcl-xL in T cells from IκBαΔN-Tg mice resulted in effective rejection of cardiac allografts and correlated with an increased frequency of splenocytes producing IFN-γ in response to alloantigen. Together, these results suggest that the death of alloreactive T cells may be partly responsible for the transplantation tolerance observed in mice with defective T cell-intrinsic NF-κB activation.

Section: Discussionmentioning

confidence: 99%

Transplantation Tolerance in NF-κB-Impaired Mice Is Not Due to Regulation but Is Prevented by Transgenic Expression of Bcl-xL

The Journal of Immunology

Balin

Mashayekhi

et al. 2005

“…+ T cells are necessary and sufficient for acute rejection of cardiac allografts (1)(2)(3)(4)(5). Although the CD4…”

Section: Introductionmentioning

confidence: 99%

Role of Natural Killer Cell Subsets in Cardiac Allograft Rejection

McNerney

Lee

American Journal of Transplantation

et al. 2006

112

To achieve donor-specific immune tolerance to allogeneic organ transplants, it is imperative to understand the cell types involved in acute allograft rejection. In wild-type mice, CD4 + T cells are necessary and sufficient for acute rejection of cardiac allografts. However, when T-cell responses are suboptimal, such as in mice treated with costimulation-targeting agents or in CD28-deficient mice, and perhaps in transplanted patients taking immunosuppressive drugs, the participation of other lymphocytes such as CD8 + T cells and NK1.1 + cells becomes apparent. We found that host NK but not NKT cells were required for cardiac rejection. Ly49G2 + NK cells suppressed rejection, whereas a subset of NK cells lacking inhibitory Ly49 receptors for donor MHC class I molecules was sufficient to promote rejection. Notably, rejection was independent of the activating receptors Ly49D and NKG2D. Finally, our experiments supported a mechanism by which NK cells promote expansion and effector function of alloreactive T cells. Thus, therapies aimed at specific subsets of NK cells may facilitate transplantation tolerance in settings of impaired T-cell function.

“…It has been shown, for example, that either CD4 π or CD8 π T cells are sufficient for induction of intestinal allograft rejection (1), whereas CD4 π T cells appear necessary and sufficient for rejection of cardiac allografts. Indeed, MHC class II-deficient mice that are devoid of CD4 π T cells or mice treated with anti-CD4 mAb cannot reject heart allografts, whereas MHC class I-deficient mice that lack the vast majority of CD8 π T cells, or wildtype mice treated with depleting anti-CD8 mAbs are fully capable of rejecting cardiac transplants (2)(3)(4)(5). These results have led to the conclusion that CD8 π T cells are not absolutely necessary for cardiac allograft rejection, although they probably participate in cardiac rejection in normal settings, as suggested by the abundant number of CD8 π T cells usually found in infiltrates from rejected grafts (6).…”

Section: Introductionmentioning

confidence: 99%

Different Mechanisms of Cardiac Allograft Rejection in Wildtype and CD28-deficient Mice

Szot

American Journal of Transplantation

Rulifson

et al. 2001

Although CD28 blockade results in long-term cardiac allograft survival in wildtype mice, CD28-deficient mice effectively reject heart allografts. This study compared the mechanisms of allogeneic responses in wildtype and CD28-deficient mice. Adoptive transfer of purified CD28-deficient T cells into transplanted nude mice resulted in graft rejection. However, this model demonstrated that the allogeneic T cell function was severely impaired when compared with wildtype T cells, despite similar survival kinetics. Cardiac allograft rejection depended on both CD4 π and CD8 π T cell subsets in CD28-deficient mice, whereas only CD4 π T cells were necessary in wildtype recipients. These results suggested that CD8 π T cells were more important in CD28-deficient than wildtype mice. In addition to the CD8 π T cell requirement, allograft rejection in CD28-deficient mice was dependent on a sustained presence of CD4 π T cells, whereas it only required the initial presence of CD4 π T cells in wildtype mice. Taken together, these data suggest that CD4 π T cells from CD28-deficient mice have impaired responses to alloantigen in vivo, thus requiring long-lasting cooperation with CD8 π T cell responses to facilitate graft rejection. These results may help to explain the failure to promote graft tolerance in some preclinical and clinical settings.