Biomedical subjects

Masayuki Sho

Publications and source records attributed to Masayuki Sho.

24 records · Page 2Linked to original sources

PubMed2003

Clinical significance of aminopeptidase N/CD13 expression in human pancreatic carcinoma.

PURPOSE: We previously established a novel murine monoclonal antibody(MH8-11) that recognized aminopeptidase N (APN)/cluster of differentiation antigen 13 (CD13). This monoclonal antibody inhibited human umbilical vein endothelial cells migration and capillary-like tube formation of human umbilical vein endothelial cells on Matrigel. In this study, we investigated the expression of APN/CD13 and the intratumor microvessel density (IMD) as the number of microvessel counts in 50 patients with pancreatic carcinoma. EXPERIMENTAL DESIGN: We investigated APN/CD13 gene expression using the reverse transcriptase-PCR. We also used immunohistochemistry with MH8-11 to investigate APN/CD13 protein expression. Moreover, we investigated the relationship between APN/CD13 expression and tumor angiogenesis by measuring the IMD. RESULTS: APN/CD13 gene expression detected by reverse transcriptase-PCR was positive in 50.0% (25 of 50) of the tumors, and APN/CD13 protein positive was detected by immunohistochemistry in 48.0% (24 of 50). APN/CD13 gene expression agreed well with the immunohistochemical findings (90.0% concordance). APN/CD13 was also significantly associated with an increase of the IMD (r = 0.71, P = 0.0003). However, APN/CD13 expression was not associated with various prognostic factors. The median survival time of patients with APN/CD13 expression was significantly shorter than that of patients without APN/CD13 expression (P = 0.009), and multivariate analysis showed that the APN/CD13 status was a significant independent factor (P = 0.016). CONCLUSIONS: Our data suggest that APN/CD13 may be a new prognostic marker for patients with pancreatic carcinoma and may have a relationship with the angiogenesis for this cancer.

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PubMed2003

[Current status and prospect of T cell costimulatory blockade in transplantation].

Organ transplantation has been widely accepted as a routine medical treatment in Japan. The recent introduction of new immunosuppressive reagents may improve outcome after transplantation. However, further investigations are required to achieve the prevention of chronic rejection and the induction of donor-specific tolerance in clinical transplantation. The potential of costimulatory blockade in controlling allograft rejection is now extensively under investigation. Although costimulatory blockade can prevent rejection and induce tolerance experimentally, there are several issues that need to be clarified before its clinical application. Recently, several novel costimulatory pathways have also been reported. Each costimulatory pathway has distinct and unique immunological roles in T cell activation and down-regulation. Upon the perception of underlying mechanisms, the theoretical and effective use of costimulatory blockade in combination with conventional immunosuppression and/or novel molecular targeting therapies might make a major breakthrough in clinical transplantation.

Animals↗

PubMed2002

T-cell response to cardiac myosin persists in the absence of an alloimmune response in recipients with chronic cardiac allograft rejection.

BACKGROUND: Immune-mediated injury to the graft has been implicated in the pathogenesis of chronic rejection. However, little is known regarding the nature of the antigen(s) involved in this immune process. We demonstrated that cardiac transplantation in mice induces an autoimmune T-cell response to a heart tissue-specific protein, cardiac myosin (CM). This response contributes to transplant rejection in that its modulation affects cardiac graft survival. This study investigates whether anti-CM T cells undergo activation and expansion in mice with chronic cardiac allograft rejection. METHODS: The frequency of CM- and donor major histocompatibility complex (MHC)-specific interferon (IFN)-gamma-producing T cells were assessed by ELISPOT in BALB/c mice, which were injected with anti-CD40L (MR1) mAb (chronic rejection group) or CTLA4Ig fusion protein (tolerant group) and transplanted with C57BL/6 cardiac allografts. RESULTS AND CONCLUSIONS: MR1-treated BALB/c recipients of C57BL/6 hearts with chronic rejection displayed a high frequency of activated CM-specific T cells, whereas the frequency of activated alloreactive T cells were similar to naïve, nontransplanted mice. In contrast, no activation of CM-reactive T cells was detected in tolerant recipients after CTLA4Ig treatment. Therefore, in the absence of alloimmunity, chronic rejection is associated with persistence of a T-cell response against CM. Our data indicate that anti-CM autoimmunity may be involved in the immune mechanisms of chronic rejection and suggest that tolerance strategies should target both allo- and autoimmune responses to prevent this process.

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PubMed2002

Physiological mechanisms of regulating alloimmunity: cytokines, CTLA-4, CD25+ cells, and the alloreactive T cell clone size.

The mechanisms underlying physiological regulation of alloimmune responses remain poorly defined. We investigated the roles of cytokines, CTLA-4, CD25(+) T cells, and apoptosis in regulating alloimmune responses in vivo. Two murine cardiac transplant models were used, B10.D2 (minor mismatch) and C57BL/6 (major mismatch), into BALB/c recipients. Recipients were wild type, STAT4(-/-) (Th1 deficient), or STAT6(-/-) (Th2 deficient) mice. Minor mismatched allografts were accepted spontaneously in approximately 70% of wild type and STAT4(-/-) mice. By contrast, there was significantly shorter graft survival in minor mismatched STAT6(-/-) mice. Either the adoptive transfer of STAT4(-/-) splenocytes or the administration of IL-4Fc fusion protein into STAT6(-/-) mice resulted in long term graft survival. Blocking CTLA-4 signaling accelerated the rejection in all recipients, but was more pronounced in the minor combination. This was accompanied by an increased frequency of alloreactive T cells. Furthermore, CTLA-4 blockade regulated CD4(+) or CD8(+) as well as Th1 or Th2 alloreactive T cells. Finally, while anti-CD25 treatment prolonged graft survival in the major mismatched combination, the same treatment accelerated graft rejection in the minor mismatched group. The latter was associated with an increased frequency of alloreactive T cells and inhibition of T cell apoptosis. These data demonstrate that cytokine regulation, CTLA-4 negative signaling, and T cell apoptosis play critical roles in regulating alloimmunity, especially under conditions where the alloreactive T cell clone size is relatively small.

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PubMed2002

New insights into the interactions between T-cell costimulatory blockade and conventional immunosuppressive drugs.

OBJECTIVE: To determine the precise in vivo interaction between T-cell costimulatory blockade and conventional immunosuppression in transplantation. SUMMARY BACKGROUND DATA: Blocking B7 or CD154 T-cell costimulatory activation pathways prevents allograft rejection in small and large animal transplant models and is considered a promising strategy for clinical organ transplantation. METHODS: A fully MHC-mismatched vascularized mouse cardiac allograft model was used to test the interactions between anti-CD154 or CTLA4Ig monotherapy and conventional immunosuppressive drugs in promoting long-term graft acceptance. The frequency of alloreactive T cell was measured by ELISPOT. Chronic rejection was examined by histology. RESULTS: Cyclosporine, tacrolimus, and anti-IL-2R monoclonal antibody therapy abrogated the effect of a single-dose protocol of anti-CD154 therapy. In contrast, rapamycin acted synergistically with anti-CD154 therapy in promoting long-term allograft survival. The addition of calcineurin inhibitors did not abolish this synergistic effect. Intense CD154-CD40 blockade by a multiple-dose schedule of anti-CD154 resulted in long-term graft survival and profound alloreactive T-cell unresponsiveness and overcame the opposite effects of calcineurin inhibitors. CTLA4Ig induced long-term graft survival, and the effect was not affected by the concomitant use of any immunosuppressive drugs. CONCLUSIONS: The widespread view that calcineurin inhibitors abrogate the effects of T-cell costimulatory blockade should be revisited. Sufficient costimulatory blockade and synergy induced by CD154 blockade and rapamycin promote allograft tolerance and prevent chronic rejection.

Abatacept↗

PubMed2002

Th1 cytokines, programmed cell death, and alloreactive T cell clone size in transplant tolerance.

The Th1 cytokines IL-2 and IFN-gamma, which inhibit T cell proliferation and promote activation induced cell death, may be required to diminish alloreactive T cell numbers and to foster tolerance across full allogeneic barriers. However, we hypothesized that these cytokines might be dispensable when the alloreactive T cell clone size is relatively small, as is seen in recipients of minor-mismatched grafts. We show that alloreactive T cell clone size of C57BL/6 mice against multiple minor-mismatched 129X1/sv mice was approximately 4-9-fold smaller than that against MHC-mismatched BALB/c mice. In the MHC-mismatched combination, CD28-B7 blockade by CTLA4Ig induced long-term graft survival in wild-type recipients, but this treatment was ineffective in IFNgamma(-/-) or IL-2(-/-) recipients. In contrast, in the minor-mismatched combination, CTLA4Ig induced long-term allograft survival in wild-type, IFNgamma(-/-), and IL-2(-/-) recipients. Bcl-x(L) transgenic animals, which are defective in "passive" T cell death, are likewise sensitive to the effects of CTLA4Ig only in the setting of the minor-mismatch grafts. Therefore, the alloreactive T cell clone size is an important determinant affecting the need for Th1 cytokines and T cell death in tolerance induction. These data have implications for the design of tolerance strategies in transplant recipients with varying degrees of MHC mismatching.

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