2000
DOI: 10.4049/jimmunol.165.12.6849
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Genetic Characterization of Strain Differences in the Ability to Mediate CD40/CD28-Independent Rejection of Skin Allografts

Abstract: Simultaneous blockade of the CD40 and CD28 T cell costimulatory pathways effectively promotes skin allograft survival in C3H/HeJ mice, extending median survival times (MSTs) beyond 100 days. This strategy is markedly less effective in C57BL/6 mice, with MSTs ranging between 20 and 30 days. In this study, we investigate the underlying genetic causes of these distinct phenotypes. Using H-2 congenic mice, we show that the genetic basis for the varied responses between these two strains is independent of the H-2 l… Show more

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Cited by 128 publications
(101 citation statements)
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“…The resistance to the effects of costimulatory blockade was alloantigen specific in that B10.A DST/aCD40L was highly effective in the presence of T cells primed to an entirely separate set of alloantigens (Table 1). Our studies confirm previously published findings that naïve CD8 π T cells (28)(29)(30)(31), T cells primed to viral antigens (32,33), and in some cases CD4 π T cells (21,34) can be resistant to the effects of costimulatory blockade. DST/aCD40L fully prevented the expansion and activation of the alloreactive T cells in naïve animals transplanted with B10.A hearts (associated with prolonged graft survival, Figure 2).…”
Section: Discussionsupporting
confidence: 91%
“…The resistance to the effects of costimulatory blockade was alloantigen specific in that B10.A DST/aCD40L was highly effective in the presence of T cells primed to an entirely separate set of alloantigens (Table 1). Our studies confirm previously published findings that naïve CD8 π T cells (28)(29)(30)(31), T cells primed to viral antigens (32,33), and in some cases CD4 π T cells (21,34) can be resistant to the effects of costimulatory blockade. DST/aCD40L fully prevented the expansion and activation of the alloreactive T cells in naïve animals transplanted with B10.A hearts (associated with prolonged graft survival, Figure 2).…”
Section: Discussionsupporting
confidence: 91%
“…Similarly, alloreactive TCR-transgenic CD8 ϩ T cells transferred into CBA hosts became activated, proliferated, and migrated to B10 cardiac allografts despite the CD154 blockade (14). Distinct recipient strains and transplant models might potentially contribute to the differential effects of CD154 blockade (24). We believe that the rejection mechanism involving different aspects of T cell function might be the key.…”
Section: Discussionmentioning
confidence: 99%
“…While initially promising, with more extensive tests of this approach the success has been somewhat limited, particularly when translated to larger animal models and to the clinic [1]. In hindsight this may not be surprising given that tolerance naturally occurs primarily in the thymus and only secondarily in the periphery [2].…”
Section: Introductionmentioning
confidence: 99%