Primed Allospecific T Cells Prevent the Effects of Costimulatory Blockade on Prolonged Cardiac Allograft Survival in Mice

Valujskikh, Anna; Pantenburg, Birte; Heeger, Peter S.

doi:10.1034/j.1600-6143.2002.20603.x

Cited by 228 publications

(223 citation statements)

References 41 publications

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“…Our current study explored a novel aspect of memory CD8 T cells, i.e., CD154 costimulation blockade-resistant activation. We and others (9,(33)(34)(35) have demonstrated that alloreactive CD8 T cells in the absence of CD4 help fail to develop this phenotype, as reactivation of helpless alloreactive CD8 memory T cells remains susceptible to the CD154 blockade suggesting that these cells are functionally naive.…”

Section: Discussionmentioning

confidence: 99%

Defective Alloreactive CD8 T Cell Function and Memory Response in Allograft Recipients in the Absence of CD4 Help

Zhai

Wang

et al. 2007

The Journal of Immunology

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We have shown that alloreactive CD8 T cell activation may proceed via CD4-dependent and CD4-independent pathways, and that CD8 T cell activation in Ag-primed animals is independent of CD154 costimulation. In this report, we further analyzed the activation and function of alloreactive CD8 CTL effectors in CD4 knockout (KO) skin/cardiac allograft recipients. FACS analysis showed that alloreactive CD8 T cells were activated at a significantly reduced level in CD4 KO mice. Importantly, these helpless CD8 T cells failed to develop CD154 blockade resistance following reactivation by the same alloantigen, indicative of defective memory formation. Only transient CD4 help was required, as short-term CD4 blockade at the time of first skin graft challenge only delayed alloreactive CD8 activation, without affecting the CD8 T cell memory response to a second skin graft. Moreover, postoperative CD4 blockade had no effect on alloreactive CD8 activation. Alloreactive CD8 cells generated in the absence of CD4 help exhibited decreased effector responses. Interestingly, intragraft induction of T cell-targeted chemokines early after transplant was also dependent on CD4 help, as the induction kinetics of CXCL9 and CCL5 in CD4 KO recipients was significantly delayed, coupled with similarly delayed infiltration by CD3/CD8 cells. Remarkably, helpless CD8 cells ultimately entering the graft still displayed significantly diminished T cell effector molecules (IFN-γ, granzyme B). Thus, CD4 help is critical for alloreactive CD8 activation, function, and memory formation.

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Section: Discussionmentioning

confidence: 99%

Defective Alloreactive CD8 T Cell Function and Memory Response in Allograft Recipients in the Absence of CD4 Help

Zhai

Wang

et al. 2007

The Journal of Immunology

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“…Taken together with our observations of combined co-stimulation blockade-resistant rejection in Tbet KO recipients mediated by T17 immunity, these data indicate that in clinical transplantation where Th1 immunity is effectively suppressed, T17 immune responses may emerge and contribute to resistance to transplantation tolerance induction with current treatment protocols. Further, T17 cells are predominantly of the memory phenotype (34,35), and memory CD8 T cells are critical in mediating resistance to co-stimulation blockade-induced transplantation tolerance (5,6). These co-stimulation blockaderesistant CD8 memory T cells could be CD8 T17 cells.…”

Section: Discussionmentioning

confidence: 99%

“…While costimulation blockade induces tolerance in less stringent mouse models of transplantation such as vascularized grafts, it is not as effective in more stringent models such as skin transplantation and in non-human primates (1). It has been suggested that, whilst CD4 T cell responses against the allograft are effectively controlled, CD8 T cells contribute to resistance to tolerance induction by costimulation blockade (2)(3)(4)(5)(6).…”

mentioning

confidence: 99%

Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells

Yuan

Ansari

D’Addio

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The ability to induce durable transplantation tolerance predictably and consistently in the clinic is a highly desired but elusive goal. Progress is hampered by lack of appropriate experimental models in which to study resistance to transplantation tolerance. Here, we demonstrate that T helper 1-associated T box 21 transcription factor (Tbet) KO recipients exhibit allograft tolerance resistance specifically mediated by IL-17-producing CD8 T (T17) cells. Neutralization of IL-17 facilitates long-term cardiac allograft survival with combined T cell co-stimulation (CD28-CD80/86 and CD154-CD40) blockade in Tbet KO recipients. We have used this T17-biased Tbet KO model of allograft tolerance resistance to study the impact of targeting a T cell-costimulatory pathway, and demonstrate that targeting T cell Ig and mucin domain-1 (Tim-1) with anti-Tim-1 overcomes this resistance by specifically inhibiting the pathogenic IL-17-producing CD8 T17 cells. These data indicate that in the absence of Th1 immunity, CD8 T17 alloreactivity constitutes a barrier to transplantation tolerance. Targeting TIM-1 provides an approach to overcome resistance to tolerance in clinical transplantation.costimulation ͉ IL-17 ͉ rejection ͉ immunosuppression

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“…Onodera et al (49), using a LBNF 1 (LEW ϫ BN F 1 hybrid) donor heart transplanted into a LEW recipients presensitized with Brown-Norway skin grafts a week before, demonstrated that grafts were rejected within 36 h. Treatment with CTLA4Ig in the sensitization phase resulted in a cardiac graft survival of 4.4 Ϯ 1.3 days, while treatment in both sensitization and effector phases prolonged survival to only 10.5 Ϯ 8.5 days. Even the highly efficacious combination of anti-CD40L Ab and DST, which can induce long-term survival of allografts in fully MHC-mismatched mouse heart transplant models, failed to prevent cardiac graft rejection in a presensitized model (50). The demonstration of very low percentages of recovered CD3 ϩ T cells from reconstituted nude recipients treated with the combination of anti-CD134 mAb and hCTLA4Ig, as compared with untreated controls and animals treated anti-CD134L mAb or hCTLA4Ig alone, suggests that only the combined therapy effectively inhibits T cell expansion and/or decreases cell survival.…”

Section: Discussionmentioning

confidence: 99%

The Role of the CD134-CD134 Ligand Costimulatory Pathway in Alloimmune Responses In Vivo

Yuan

Salama

Dong

et al. 2003

The Journal of Immunology

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The CD134-CD134 ligand (CD134L) costimulatory pathway has been shown to be critical for both T and B cell activation; however, its role in regulating the alloimmune response remains unexplored. Furthermore, its interactions with other costimulatory pathways and immunosuppressive agents are unclear. We investigated the effect of CD134-CD134L pathway blockade on allograft rejection in fully MHC-mismatched rat cardiac and skin transplantation models. CD134L blockade alone did not prolong graft survival compared with that of untreated recipients, and in combination with donor-specific transfusion, cyclosporine, or rapamycin, was less effective than B7 blockade in prolonging allograft survival. However, in combination with B7 blockade, long-term allograft survival was achieved in all recipients (>200 days). Moreover, this was synergistic in reducing the frequency of IFN-γ-producing alloreactive lymphocytes and inhibiting the generation of activated/effector lymphocytes. Most impressively, this combination prevented rejection in a presensitized model using adoptive transfer of primed lymphocytes into athymic heart transplant recipients. In comparison to untreated recipients (mean survival time (MST): 5.3 ± 0.5 days), anti-CD134L mAb alone modestly prolonged allograft survival (MST: 14 ± 2.8 days) as did CTLA4Ig (MST: 21.5 ± 1.7 days), but all grafts were rejected within 24 days. Importantly, combined blockade further and significantly prolonged allograft survival (MST: 75.3 ± 12.7 days) and prevented the expansion and/or persistence of primed/effector alloreactive T cells. Our data suggest that CD134-CD134L is a critical pathway in alloimmune responses, especially recall/primed responses, and is synergistic with CD28-B7 in mediating T cell effector responses during allograft rejection. Understanding the mechanisms of collaboration between these different pathways is important for the development of novel strategies to promote long-term allograft survival.

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Primed Allospecific T Cells Prevent the Effects of Costimulatory Blockade on Prolonged Cardiac Allograft Survival in Mice

Cited by 228 publications

References 41 publications

Defective Alloreactive CD8 T Cell Function and Memory Response in Allograft Recipients in the Absence of CD4 Help

Defective Alloreactive CD8 T Cell Function and Memory Response in Allograft Recipients in the Absence of CD4 Help

Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells

The Role of the CD134-CD134 Ligand Costimulatory Pathway in Alloimmune Responses In Vivo

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