FasL IS IMPORTANT IN COSTIMULATION BLOCKADE-RESISTANT SKIN GRAFT REJECTION

Trambley, Joel; Lin, Angello; Elwood, Eric T.; Bingaman, Adam W.; Lakkis, Fadi G.; Corbascio, Matthias; Pearson, Thomas C.; Larsen, Christian

doi:10.1097/00007890-200102270-00009

Cited by 7 publications

(8 citation statements)

References 28 publications

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“…Although the Fas–FasL pathway plays a vital role in mediating the process of activation‐induced cell death, previous studies in lpr and gld mice and our findings (Fig. ) suggest that the Fas–FasL apoptotic pathway is not crucial for the deletion of alloreactive T cells during tolerance induction.…”

Section: Discussioncontrasting

confidence: 59%

“…These findings suggest that alloreactive T cells prevented from undergoing deletion during co-stimulation blockade by exposure to inflammation remain susceptible to apoptotic stimuli. Although the Fas-FasL pathway plays a vital role in mediating the process of activation-induced cell death, previous studies in lpr and gld mice [35][36][37] and our findings ( Fig. 4) suggest that the Fas-FasL apoptotic pathway is not crucial for the deletion of alloreactive T cells during tolerance induction.…”

Section: Discussioncontrasting

confidence: 57%

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Alloreactive CD8 T cells rescued from apoptosis during co‐stimulation blockade by Toll‐like receptor stimulation remain susceptible to Fas‐induced cell death

et al. 2013

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SummaryBlockade of co-stimulatory signals to T cells is extremely effective for the induction of transplantation tolerance in immunologically naive rodents. However, infections and inflammation compromise the efficacy of co-stimulation blockade regimens for the induction of tolerance, thereby stimulating the rejection of allografts. Previous studies have shown that stimulation of innate immunity abrogates tolerance induction by preventing the deletion of alloreactive CD8 + T cells that normally occurs during co-stimulation blockade. Although inflammation prevents the deletion of alloreactive T cells during co-stimulation blockade, it is not known if this resistance to cell death is the result of a mechanism intrinsic to the T cell. Here, we used syngeneic bone marrow chimeric mice that contain a trace population of T-cell receptor transgenic alloreactive CD8 + T cells to investigate the early apoptotic signature and activation status of alloreactive T cells following exposure to inflammatory signals during co-stimulation blockade with an antibody specific for CD154. Our findings revealed that the presence of bacterial lipopolysaccharide during co-stimulation blockade enhanced the early activation of alloreactive CD8 + T cells, as indicated by the up-regulation of CD25 and CD69, suppressed Fas ligand expression, and prevented apoptotic cell death. However, alloreactive CD8 + T cells from lipopolysaccharide-treated mice remained sensitive to Fas-mediated apoptosis in vitro. These findings suggest that alloreactive T cells rescued from deletion during co-stimulation blockade by inflammation are still sensitive to proapoptotic signals and that stimulating these apoptotic pathways during co-stimulation blockade may augment the induction of tolerance.

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Section: Discussioncontrasting

confidence: 59%

Section: Discussioncontrasting

confidence: 57%

Alloreactive CD8 T cells rescued from apoptosis during co‐stimulation blockade by Toll‐like receptor stimulation remain susceptible to Fas‐induced cell death

et al. 2013

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“…This has been supported by recent studies in which a Fas-Fc-receptor construct or specific caspace inhibitors blocked T-cell co-stimulation (30). In an allograft model we have found that combined blockade of the CD28 and CD40 pathways resulted in prolonged allograft survival in FasL-deficient mice compared with wild-type mice (31). These data suggest that manipulation of the Fas pathway may be a useful component of strategies that promote the acceptance of transplanted organs.…”

Section: Fas and Fas Ligandsupporting

confidence: 63%

“…Although a complete review of the known effects of TNFR/TNF superfamily members in the development and regulation of the immune system is beyond the scope of this article, interested readers are referred to two recent reviews (8,9). Members of the TNFR superfamily are defined by the homology of their extracellular domains particularly with respect to a specific repetitive pattern of cys- Table 1: Summary of reviewed TNFR superfamily molecules and their ligands Receptor Distribution Ligand TNF Distribution Properties TNFR superfamily superfamily (references pertaining to transplantation) FAS (CD95, T and B cells, APC, FASL T cells, APC, and Involved in peripheral T-cell homeostasis via APO-1) and stromal cells (TNFSF6) stromal cells 'fratricide', may deliver co-stimulatory signal (TNFRSF6) (27,28,31) teine residues. The cytoplasmic region of TNFR superfamily members can be categorized by the presence or absence of a death domain that, upon engagement of the receptor by the appropriate ligand, can induce apoptosis (i.e.…”

Section: Introductionmentioning

confidence: 99%

The Role of TNF Receptor and TNF Superfamily Molecules in Organ Transplantation

Adams

Larsen

Pearson

et al. 2002

American Journal of Transplantation

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The rapid increase in the number of molecules demonstrated to regulate immune responses has provided new opportunities for manipulation of the recipient immune response to transplanted organs. Molecules belonging to the TNF receptors and TNF superfamily are increasingly recognized as playing a major role in the regulation of immune responses to tumor, viral, and autoantigens. The mechanisms by which these molecules regulate immune responses are diverse. TNF receptor-related molecules have been shown to control the development of secondary lymphoid organs, affect the activation and survival of T cells and antigen presenting cells, and alter cytokine and chemokine production. An increasing amount of data suggest that some TNFR superfamily members are particularly important for the function of CD8 π T cells. Based on our current understanding of these molecules it seems highly likely that strategies that target selected TNFR/ TNF superfamily molecules will be useful for controlling or preventing the rejection of transplanted organs and tissues.

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“…The integrity of activation induced cell death (AICD) and passive cell death (PCD) pathways is critical for allograft tolerance with treatments that do not permanently or totally eradicate donor reactive effector T cells, such as costimulation blockade (17–19). The widely used immunosuppressive drug cyclosporine interferes with AICD of effector T cells (19–21) and is detrimental to tolerance induction when used as an adjunct to a costimulation blockade based regimen (17,18,22). However, in our previous studies, the impact of cyclosporine on T regs has not been investigated.…”

Section: Introductionmentioning

confidence: 99%