| 1. |
- Dai, Helong, et al.
(författare)
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Blockade of CD27/CD70 pathway to reduce the generation of memory T cells and markedly prolong the survival of heart allografts in presensitized mice
- 2011
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Ingår i: Transplant Immunology. - : Elsevier BV. - 1878-5492 .- 0966-3274. ; 24:4, s. 195-202
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alloreactive memory T cells are a major obstacle to transplantation acceptance due to their capacity for accelerated rejection. Methods: 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. Results: 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 +/- 428% 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 10 days to more than 90 days (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). Conclusions: 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. (C) 2011 Elsevier B.V. All rights reserved.
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| 2. |
- Lin, Yingying, et al.
(författare)
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Arsenic trioxide is a novel agent for combination therapy to prolong heart allograft survival in allo-primed T cells transferred mice
- 2011
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Ingår i: Transplant Immunology. - : Elsevier BV. - 1878-5492 .- 0966-3274. ; 25:4, s. 194-201
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Tidskriftsartikel (refereegranskat)abstract
- Alloreactive memory T cells are major barriers to transplantation acceptance due to their capacity to accelerate rejection. Here, we investigated the effects of combined treatment with arsenic trioxide (As(2)O(3)) and blocking monoclonal antibodies (mAb) against CD154 and LFA-1 (anti-CD154/LFA-1) on graft survival as well as changes in pathology and immunological responses in mice with adoptively transferred allo-primed T cells. The mean survival time (MST) for the cardiac allografts in recipient mice receiving the combination of As(2)O(3) and anti-CD154/LFA-1 was significantly longer (>113.7 days) compared to those receiving anti-CD154/LFA-1 (232 days), As(2)O(3) (12.5 days) alone or no treatment (5.5 days). This combined strategy distinctly inhibited lymphocyte infiltration in grafts, proliferation of splenic T cells and the generation of memory T cells in spleens. Moreover, the combined treatment caused the significant down-regulation of IL-2 and IFN-gamma accompanied by increased expression of TGF-beta and regulatory T cells (Tregs) in spleens, which led to long-term cardiac allograft survival in recipient mice. These results highlight the potential application of As(2)O(3) and its contribution in combination therapy with antibody blockade to delay rejection by memory T cells. (C) 2011 Elsevier B.V. All rights reserved.
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| 3. |
- Ma, Yunhan, et al.
(författare)
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Leflunomide Inhibits rat-to-Mouse Cardiac Xenograft Rejection by Suppressing Adaptive Immune Cell Response and NF-κB Signaling Activation
- 2021
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Ingår i: Cell Transplantation. - : SAGE Publications. - 0963-6897 .- 1555-3892. ; 30
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Tidskriftsartikel (refereegranskat)abstract
- Xenotransplantation is a potential solution for the severe shortage of human donor organs and tissues. The generation of humanized animal models attenuates strong innate immune responses, such as complement-mediated hyperacute rejection. However, acute vascular rejection and cell mediated rejection remain primary barriers to xenotransplantation, which limits its clinical application. In this study, we systematically investigated the immunosuppressive effect of LEF using a rat-to-mouse heart xenotransplantation model. SD rat xenogeneic hearts were transplanted into C57BL/6 mice, and survived 34.5 days after LEF treatment. In contrast, BALB/c allogeneic hearts were transplanted into C57BL/6 mice, and survived 31 days after LEF treatment. Compared to normal saline treatment, LEF treatment decreased xenoreactive T cells and CD19+ B cells in recipient splenocytes. Most importantly, LEF treatment protected myocardial cells by decreasing xenoreactive T and B cell infiltration, inflammatory gene expression, and IgM deposition in grafts. In vivo assays revealed that LEF treatment eliminated xenoreactive and alloreactive T and B lymphocytes by suppressing the activation of the NF-κB signaling pathway. Taken together, these observations complement the evidence supporting the potential use of LEF in xenotransplantation.
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| 4. |
- Shao, Wei, et al.
(författare)
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CD44/CD70 blockade and anti-CD154/LFA-1 treatment synergistically suppress accelerated rejection and prolong cardiac allograft survival in mice.
- 2011
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 74, s. 430-437
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Tidskriftsartikel (refereegranskat)abstract
- Current treatments that are efficient in controlling effector T cells responses to allografts have limited efficacy on the accelerated rejection mediated by memory T cells. Effective targeting of alloreactive memory T cells may therefore be explored to improve therapeutic approaches towards solving this problem. In this study, we investigated the synergistic effect of CD44/CD70 blockade and anti-CD154/LFA-1 treatment on the accelerated rejection mediated by memory T cells. While CD44/CD70 blockade had limited effects on the alloresponses of effector T cells in vivo, it diminished the expansion of both CD4(+) and CD8(+) memory T cells in recipients adoptively transferred with donor-sensitized T cells. In combination with anti-CD154/LFA-1 treatment, CD44/CD70 blockade significantly prolonged cardiac allograft survival in adoptive transfer recipients. We demonstrated that treatment with the combination of all four antibodies (anti-CD154/LFA-1/CD44/CD70) inhibited accelerated rejection by markedly suppressing the alloresponses of effector and memory T cells and reducing the number of graft-infiltration lymphocytes in adoptive transfer recipients. Meanwhile, CD44/CD70 blockade and anti-CD154/LFA-1 treatment synergically enhanced regulatory T cells (Tregs) by increasing the proportion of splenic Tregs and the expression of IL-10 in these recipients. Our findings contribute to the potential design of therapies for accelerated allograft rejection.
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| 5. |
- Shao, Wei, et al.
(författare)
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Combination of monoclonal antibodies with DST inhibits accelerated rejection mediated by memory T cells to induce long-lived heart allograft acceptance in mice
- 2011
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Ingår i: Immunology Letters. - : Elsevier BV. - 0165-2478. ; 138:2, s. 122-128
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Tidskriftsartikel (refereegranskat)abstract
- Donor-reactive memory T cells mediated accelerated rejection is known as a barrier to the survival of transplanted organs. We investigated the combination of different monoclonal antibodies (mAbs) and donor-specific transfusion (DST) in memory T cells-based adoptive mice model. In the presence of donor reactive memory T cells, the mean survival time (MST) of grafts in the anti-CD40L/LFA-1/DST group was 49.8 d. Adding anti-CD44/CD70 mAbs to anti-CD40L/LFA-1/DST treatment. The MST was more than 100 d (MST > 100 d). Compared with anti-CD40L/LFA-1/DST group, anti-CD40L/LFA-1/CD44/CD70/DST group notably reduced the expansion of memory T cells, enhanced the proportion of CD4(+)Foxp3(+) regulatory T cells (Tregs) and suppressed donor-specific responses. Our data suggest that anti-CD40L/LFA--1/CD44/CD70 mAbs and DST can synergistically inhibit accelerated rejection mediated by memory T cells to induce long-lived heart allograft acceptance in mice. (C) 2011 Elsevier B.V. All rights reserved.
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| 6. |
- Wang, Feng, et al.
(författare)
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The major histocompatibility complex (MHC) of the secondary transplant tissue donor influences the cross-reactivity of alloreactive memory cells.
- 2011
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 73, s. 190-197
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Tidskriftsartikel (refereegranskat)abstract
- Memory cells are currently thought to be a major barrier to tolerance induction in transplantation. However, whether alloreactive memory cells resulting from a primary transplant have cross-reactivity in a second transplant is unclear. Here, we used skin transplantation from BALB/c mice donors to pre-sensitize C(57) BL/6 (B6) mice. One month later, several strains of mice (including BALB/c, DBA/2, NOD, C3H and B6 mice) were chosen as donors to construct a memory model of heterotopic cardiac transplantation. The higher degree of MHC mismatch to sensitizing MHC resulted in longer Median survival times (MSTs, BALB/c 3.63 days VS C3H 6.08 days). 3.5 days after cardiac transplantation, compared with the BALB/c and DBA/2 groups, in the groups of NOD and C3H, the infiltration of inflammatory cells in the grafts, the proportion and proliferation of memory cells in spleens, and the function of allogeneic antibodies decreased significantly. The varying degrees of MHC mismatch between the primary and secondary donors influenced the intensity of alloreactive memory cell function, the higher degree of MHC mismatch resulted in better tolerance during secondary transplantation, and these may be related to the changed activation, proliferation and function of the alloreactive memory cells.
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