Blockade of CD27/CD70 pathway to reduce the generation of memory T cells and markedly prolong the survival of heart allografts in presensitized mice
ABSTRACT Alloreactive memory T cells are a major obstacle to transplantation acceptance due to their capacity for accelerated rejection.
C57BL/6 mice that had rejected BALB/c skin grafts 4 weeks earlier were used as recipients. The recipient mice were treated with anti-CD154/LFA-1 with or without anti-CD70 during the primary skin transplantation and anti-CD154/LFA-1 or not during the secondary transplantation of BALB/c heart. We evaluated the impact of combinations of antibody-mediated blockade on the generation of memory T cells and graft survival after fully MHC-mismatched transplantations.
One month after the primary skin transplantation, the proportions of CD4(+) memory T cells/CD4(+) T cells and CD8(+)memory T cells/CD8(+) T cells in the anti-CD154/LFA-1 combination group were 47.32±4.28% and 23.18±2.77%, respectively. In the group that included anti-CD70 treatment, the proportions were reduced to 34.10±2.71% and 12.19±3.52% (P<0.05 when comparing the proportion of memory T cells between the two groups). The addition of anti-CD70 to the treatment regimen prolonged the mean survival time following secondary heart transplantation from 10days to more than 90days (P<0.001). Furthermore, allogenic proliferation of recipient splenic T cells and graft-infiltrating lymphocytes were significantly decreased. Meanwhile, the proportion of regulatory T cells was increased to 9.46±1.48% on day 100 post-transplantation (P<0.05).
The addition of anti-CD70 to the anti-CD154/LFA-1 combination given during the primary transplantation reduced the generation of memory T cells. This therapy regimen provided a potential means to alleviate the accelerated rejection mediated by memory T cells during secondary heart transplantation and markedly prolong the survival of heart allografts.
- SourceAvailable from: Juan Carlos Kaski
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- "Surprisingly, this effect was not mediated by inhibition of T-cell activation but was attributed to a decrease in the production of TNF-α. Similarly, blockade of the CD27/CD70 pathway prolonged the survival of heart allografts . In this study, treatment with anti-CD70 antibodies reduced the generation of memory T cells and resulted in decreased infiltration of allografts by effector CD4 + T cells. "
ABSTRACT: Atherosclerosis is a chronic inflammatory disease that is mediated by both the innate and adaptive immune responses. T lymphocytes, that together with B cells are the cellular effectors of the adaptive immune system, are currently endowed with crucial roles in the development and progression of atherosclerosis. Costimulatory receptors are a class of molecules expressed by T lymphocytes that regulate the activation of T cells and the generation of effector T-cell responses. In this review we present the roles of costimulatory receptors of the tumour necrosis factor receptor (TNFR) superfamily in atherosclerosis and discuss the implications for future therapies that could be used to specifically modulate the immune response of pathogenic T cells in this disease.BioMed Research International 01/2012; 2012:464532. DOI:10.1155/2012/464532 · 2.71 Impact Factor
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ABSTRACT: BACKGROUND: Accelerated rejection is a type of refractory rejection. Animal models of accelerated rejection are widely employed in research on transplant immunity. METHODS: We divided 36 C57BL/6 mice into six groups that underwent heart transplant. To select the ideal number of splenocytes for the presensitization to induce accelerated rejection, were transferred 0.5 × 10(7), 1 × 10(7), 5 × 10(7), or 10 × 10(7) donor splenocytes 7 d before transplantation. We confirmed successful presensitization by increases in donor-reactive antibodies. We performed 12 additional heart transplants in the accelerated rejection group and the control groups for a histological examination, immunohistochemical staining for C3d, and a splenocyte test using flow cytometry. RESULTS: The transfer of 5 × 10(7) donor splenocytes effectively and efficiently induced an accelerated rejection in the BALB/c→C57BL/6 heart transplant, with an allograft survival time that was decreased from 7.4 ± 0.5 d to 3.5 ± 0.8 d compared with the allogenic controls (P < 0.05, log-rank test). An analysis of this model indicated that compared with acute rejection, the number of donor-reactive antibodies was significantly increased, and the proportions of effector memory CD8(+) T cells and plasmacytes in the spleen were significantly increased (7.81% ± 1.2% versus 2.96% ± 1.0%, P = 0.006; 1.27% ± 0.13% versus 0.71% ± 0.22%, P = 0.018, respectively). We found the histological characteristics of both cellular and humoral rejection in the accelerated rejection model. CONCLUSIONS: Presensitization via the transfer of donor splenocytes facilitates the establishment of an accelerated rejection model. Our findings with this model indicate that humoral rejection and cellular rejection are coexistent, and that the proportions of effector memory CD8(+) T cells and plasmacytes in the spleen increase significantly during accelerated rejection.Journal of Surgical Research 05/2012; 181(1). DOI:10.1016/j.jss.2012.05.031 · 2.12 Impact Factor
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ABSTRACT: CD27 interactions with its ligand, CD70, are thought to be necessary for optimal primary and memory adaptive immune responses to a variety of pathogens. Thus far, all studies addressing the function of the CD27-CD70 axis have been performed in mice lacking CD27, in those overexpressing CD70, or in those in which these molecules were blocked or mimicked by Abs or recombinant soluble CD70. Because these methods have in some cases led to divergent results, we generated CD70-deficient mice to directly assess its role in vivo. We find that lack of CD70-mediated stimulation during primary responses to lymphocytic choriomeningitis virus lowered the magnitude of CD8 Ag-specific T cell response, resulting in impaired viral clearance, without affecting CD4 T cell responses. Unexpectedly, CD70-CD27 costimulation was not needed for memory CD8 T cell generation or the ability to mount a recall response to lymphocytic choriomeningitis virus. Adoptive transfers of wild-type memory T cells into CD70(-/-) or wild-type hosts also showed no need for CD70-mediated stimulation during the course of the recall response. Moreover, CD70 expression by CD8 T cells could not rescue endogenous CD70(-/-) cells from defective expansion, arguing against a role for CD70-mediated T:T help in this model. Therefore, CD70 appears to be an important factor in the initiation of a robust and effective primary response but dispensable for CD8 T cell memory responses.The Journal of Immunology 12/2012; 190(3). DOI:10.4049/jimmunol.1202353 · 5.36 Impact Factor