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Biomedical subjects

H Bashuda

Publications and source records attributed to H Bashuda.

15 recordsLinked to original sources
PubMed2001

Induction of hyporesponsiveness to fully allogeneic cardiac grafts by intratracheal delivery of alloantigen.

BACKGROUND: Soluble protein delivered through the mucosal surface can induce immunological unresponsiveness. The purpose of this study was to determine if prior exposure to alloantigen via the trachea could modulate the immune response to subsequent cardiac allografts. METHODS: Hearts from C57BL/10(H2b) mice were transplanted into CBA(H2k) recipients. Recipient mice were given donor 1x10(7) splenocytes into the trachea with or without antibody specific for mouse CD80 (1G10) and/or CD86 (GL1) (100 microg each) 7 days before transplantation. RESULTS: All grafts survived in recipients treated with intratracheal delivery of alloantigen for over 35 days (mean survival time [MST], 56 days), whereas naive control mice and mice treated with syngeneic antigen rejected grafts acutely (MST, 8 and 7 days, respectively). Interestingly, when 1G10, GL1, or both of them were combined with the protocol, the majority of grafts were rejected within 21 days after grafting (MST, 7, 15, and 17 days, respectively). CONCLUSION: Intratracheal delivery of alloantigen induced significantly prolonged survival of fully mismatched cardiac allografts and the effect was abrogated by the blockade CD80 and/or CD86 pathway.

Animals↗
PubMed2001

Requirement for natural killer T (NKT) cells in the induction of allograft tolerance.

In this study, we investigated the role of Valpha14 natural killer T (NKT) cells in transplant immunity. The ability to reject allografts was not significantly different between wild-type (WT) and Valpha14 NKT cell-deficient mice. However, in models in which tolerance was induced against cardiac allografts by blockade of lymphocyte function-associated antigen-1/intercellular adhesion molecule-1 or CD28/B7 interactions, long-term acceptance of the grafts was observed only in WT but not Valpha14 NKT cell-deficient mice. Adoptive transfer with Valpha14 NKT cells restored long-term acceptance of allografts in Valpha14 NKT cell-deficient mice. The critical role of Valpha14 NKT cells to mediate immunosuppression was also observed in vitro in mixed lymphocyte cultures in which lymphocyte function-associated antigen-1/intercellular adhesion molecule-1 or CD28/B7 interactions were blocked. Experiments using IL-4- or IFN-gamma-deficient mice suggested a critical contribution of IFN-gamma to the Valpha14 NKT cell-mediated allograft acceptance in vivo. These results indicate a critical contribution of Valpha14 NKT cells to the induction of allograft tolerance and provide a useful model to investigate the regulatory role of Valpha14 NKT cells in various immune responses.

Adaptation, Physiological↗
PubMed2000

Graft vasculopathy and tolerance: does the balance of Th cells contribute to graft vasculopathy?

BACKGROUND: Cardiac allograft vasculopathy (CAV) is sometimes observed even though the allograft may survive indefinitely. In this study, we examined whether or not the preferential activation of Th2-type cells prevents the development of CAV. METHODS: Hearts from C57BL/10 mice were transplanted heterotopically into the abdominal cavities of C3H.He recipient mice, and monoclonal antibodies (mAbs) to T-cell receptor (TCR) alphabeta or CD80/CD86 were administered after transplantation. The incidence of CAV was then examined histologically. To investigate the relative Th1/Th2 balance, the levels of IFNgamma and IL4 in the transplanted hearts were measured. RESULTS: Indefinite heart graft survival was observed in mice treated with either the anti-TCRalphabeta or anti-CD80/CD86 mAbs and these mice accepted donor-type (C57BL/10) skin grafts but rejected those from a third party (BALB/c). Evidence of CAV was found in the mice treated with the anti-TCRalphabeta mAb, but CAV did not develop in the mice treated with anti-CD80/CD86 mAbs. Preferential activation of Th2-type cells was dominant in the tolerant mice treated with anti-TCRalphabeta mAb, but it was not dominant in the tolerant mice treated with anti-CD80/CD86 mAbs. CONCLUSION: These findings suggest that the dominance of Th2-type cells does not prevent allograft vasculopathy.

Adoptive Transfer↗
PubMed1998

A crucial role of host CD80 and CD86 in rat cardiac xenograft rejection in mice.

BACKGROUND: Graft rejection can be initiated by two primary pathways of antigen presentation: (a) direct activation of host T cells by donor-derived antigen presenting cells (APC) and (b) indirect presentation of processed graft antigens by host APC. METHODS: We investigated the differential roles for direct and indirect antigen presentation by preventing the CD28 costimulatory pathway with monoclonal antibodies to rat or mouse CD80 and CD86 in a rat-to-mouse cardiac transplantation model. RESULTS: Although the mouse anti-rat monoclonal antibodies to CD80 and CD86 did not significantly prolong the survival of rat cardiac xenografts in mice, the rat anti-mouse monoclonal antibodies to CD80 and CD86 did prolong the survival. Development of the anti-donor antibodies was inhibited, and the deposition of C3, IgM, and IgG on endothelium in the xenografts was mild in the anti-mouse CD80/CD86-treated mice. Infiltration of macrophages, neutrophils, and lymphocytes expressing perforin and interferon-gamma was decreased by the anti-mouse CD80/CD86 treatment. CONCLUSIONS: These findings suggest that the indirect antigen presentation, which is mediated by CD80 and CD86 pathway on host APC, plays a crucial role in concordant cardiac xenograft rejection.

Animals↗
PubMed1998

Improvement in nerve regeneration by monoclonal antibodies to ICAM-1 and LFA-1 in allogeneic mice.

We examined whether giving monoclonal antibodies (MoAb) to intercellular adhesion molecule 1 (ICAM-1) and leucocyte function associated antigen (LFA-1), which have important roles in the initial stage of rejection after allografts, can improve nerve regeneration in allogeneic mice. Fresh sciatic nerves were grafted using BALB/c mice as donors and C3H/He mice as recipients. Nerve regeneration at six weeks was significantly better in the mice given MoAbs at one and five days than in those given none (n = 5 in each group), although nerve regeneration even in the five-day group was significantly inferior to that in the syngeneic nerve graft group (n = 5). The survival time of the nerve donor skin graft at 12 weeks was not prolonged by treatment with MoAbs, indicating a failure to induce immunological tolerance. However, at 10 months after nerve grafting there were fewer Mac-1, Lyt-1, and Thy-1 positive cells in the five-day group and they showed less immunoreactivity than the untreated group. We conclude that giving MoAbs could effectively improve nerve regeneration in grafted allogeneic nerve segments, although it did not induce immunological tolerance.

Animals↗
PubMed1997

Lack of cognate help by CD4+ T cells and anergy of CD8+ T cells are the principal mechanisms for anti-leukocyte function-associated antigen-1/intercellular adhesion molecule-1-induced cardiac allograft tolerance.

Combined treatment with anti-leukocyte function-associated antigen-1 (LFA-1) and anti-intercellular adhesion molecule-1 (ICAM-1) monoclonal antibodies leads to allograft tolerance in murine cardiac transplantation. In the present study, we analyzed the mechanisms for this tolerance induction. In the tolerant mice, proliferative response of splenic T cells against donor-type cardiac myocytes and of CD8+ T cells against donor-type alloantigens was impaired as compared with responses in naive or rejected mice, but was completely restored with exogenous interleukin 2. This suggests that class I-restricted CD8+ T cells of tolerant mice were rendered anergic against donor-type alloantigens in the periphery. In contrast, proliferative response of CD4+ T cells against donor-type alloantigens in vitro was comparable between tolerant and naive mice. When heart and skin grafts from the same donor (BALB/c [H2d]) were simultaneously transplanted to C3H mice (H2k), both were rejected within 29 days, even though the mice were similarly treated with anti-LFA-1 and anti-ICAM-1 monoclonal antibodies. In contrast, when heart graft from BALB/c and skin graft from third-party donor (C57BL/6 [H2b]) were simultaneously transplanted to C3H mice under the same condition, the heart graft was accepted indefinitely and the skin graft was rejected. These findings suggest that the peripheral tolerance against cardiac allografts could be induced by selective inactivation of alloreactive CD8+ T cells resulting from the lack of cognate help by CD4+ T cells.

Animals↗
PubMed1996

Induction of persistent allograft tolerance in the rat by combined treatment with anti-leukocyte function-associated antigen-1 and anti-intercellular adhesion molecule-1 monoclonal antibodies, donor-specific transfusion, and FK506.

We previously reported that a short course of treatment with anti-LFA-1 and anti-ICAM-1 monoclonal antibodies (mAbs) led to a persistent acceptance of mouse cardiac allografts, which resulted from the induction of allospecific tolerance. In the present study, we tested the effect of anti-LFA-1 and anti-ICAM-1 mAbs on rat allograft rejection and analyzed the mechanisms underlying allograft tolerance. In sharp contrast to the mouse case, a short course of treatment with anti-LFA-1 and anti-ICAM-1 mAbs led to a persistent acceptance in only half of the treated rats when MHC was compatible but mismatched for minor antigens, and was virtually ineffective when MHC was fully incompatible. However, treatment with these mAbs combined with donor-specific transfusion and FK506 consistently led to a persistent acceptance, even when the MHC was fully incompatible. Donor-specific tolerance was induced by this treatment, as estimated by skin challenging. In the tolerant rats, proliferative response and CTL generation against donor-type alloantigen were severely impaired but partially restored by exogenous interleukin-2. Limiting dilution analysis demonstrated that the precursor frequency of CTL was decreased in the tolerant rats, as compared with the naive rats. These results suggest that donor-reactive T cells were partially deleted and rendered anergic in the periphery.

Animals↗
PubMed1996

Contribution of Fas ligand to cardiac allograft rejection.

Effector mechanisms for allograft injury remain unclear. In the present study, we verified the contribution of Fas and Fas ligand (FasL) to cardiac allograft rejection by utilizing the Fas-deficient lpr or FasL-deficient gld mice as the donor or recipient. Cardiac myocytes prepared from normal mice, but not those from lpr mice, constitutively expressed Fas and were susceptible to FasL-mediated lysis. Survival of cardiac allografts was substantially prolonged when gld or lpr mice were used as the recipient. In contrast, cardiac allografts from lpr mice were normally rejected without a delay. Histological examination of the grafts in the gld or lpr recipients demonstrated a lesser cellular infiltration and much milder myocyte damage. Proliferative response and cytotoxic T lymphocyte induction against the donor-type alloantigens were not impaired in the gld or lpr recipients. These results indicate a substantial contribution of FasL to cardiac allograft rejection, independent of Fas in the grafts. This ralses a possibility that FasL may be more generally involved in tissue damage associated with various diseases than expected from the expression of Fas in the target organs.

Animals↗
PubMed1995

CAM--a novel immunosuppressive agent.

This is an initial study of the immunosuppressive efficacy of CAM, a derivative of mycophenolic acid, in a rat heart allograft model when the major histocompatibility complex was fully incompatible, and its effect in improving heart allograft survival compared with mycophenolate mofetil (MMF, RS-61443). CAM or MMF was administered orally from day 1 following the allografting for 40 days. The median survival times (MST) were 6 days in rats with no immunosuppressive drug (control group; n = 6), 83 days with CAM 10 mg/kg (n = 6), and > 100 days with both 20 mg/kg (n = 7), and 30 mg/kg (n = 10). With MMF, in contrast, MST was 9, 17, 35, days with 10, 20, 30 mg/kg/day, respectively. All grafts in the CAM 30 mg/kg-treated group survived for more than 100 days after grafting, and, furthermore, CAM was also more effective than MMF in prolongation of the heart graft survival in rats at each dose. Rats with long-surviving cardiac allografts (30 mg/kg; CAM) accepted skin grafts from the donor-strain but rejected them from the third-party strain, suggesting that donor-specific tolerance was induced by CAM. In the tolerant rats, proliferative response against donor-type alloantigen was not impaired as compared with naive WKAH rats. In contrast, CML assay showed that T cells obtained from the rats bearing permanently accepted F344 heart grafts had less cytotoxic activity to the donor-type target, and the frequency of CTL precursor against donor-type alloantigen was also reduced.

Animals↗
PubMed1995

Prevention of fetal bowel allograft rejection by combined treatment with anti-ICAM-1 and anti-LFA-1 antibodies.

Prevention and treatment of allograft rejection remain the major issues in clinical small bowel transplantation. New strategies for manipulating immune responses using more powerful immunosuppressive agents continue to be evaluated. The fetal small bowel from BALB/c (H-2d) or C3H/He (H-2k) mice was transplanted into the space between the peritoneum and rectus abdominis of adult C3H/He (H-2k) recipient mice. Syngeneic (n = 6) and allogeneic transplant groups were made. In the allogeneic group, the recipient mice were subdivided into three groups, depending on the duration of combined treatment with anti-LFA-1 and anti-ICAM-1 monoclonal antibodies (MAbs): untreated (n = 10), 7-day course (n = 10), and 4-week course (n = 14). A dose of 50 micrograms/mouse/d each of both MAbs was given intraperitoneally, immediately after transplantation and on the consecutive days. All mice were killed 4 weeks after transplantation, and the graft as well as the recipient spleen were taken for histological examination, graft survival ratio, mixed lymphocyte reaction (MLR) assay and cytotoxic T lymphocyte (CTL) assay. All grafts in the syngeneic group survived with normal villi, whereas all grafts in the allogeneic group without treatment disappeared within 4 weeks. All grafts in the allogeneic group with a 7-day course of MAb treatment showed marked disruption of the mucosa with massive cellular infiltration. However, in the allogeneic group treated for 4 weeks, all allografts had adequate growth and demonstrated normal villi with minimal cellular infiltration. Splenocytes from allografted recipient mice without MAb treatment showed markedly increased MLR and CTL activity, compared with the activity seen in the syngeneic MLR and CTL.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

CD86 (B70/B7-2) on endothelial cells co-stimulates allogeneic CD4+ T cells.

In vascularized organ transplantation, vascular endothelial cells (EC) confronting recipient T cells are potentially significant APC initiating cellular immune responses that lead to rejection. In the present study, we studied the ability of human EC to stimulate allogeneic T cells and the co-stimulatory molecules involved in this response. On both human umbilical vein endothelial cells (HUVEC) and microvascular endothelial cells (MVEC), MHC class I, intercellular adhesion molecule (ICAM)-1 and CD86 were constitutively expressed as assessed by flow cytometry. After IFN-gamma treatment, MHC class II expression was induced, and MHC class I and ICAM-1 were up-regulated. In contrast, the expression of CD86 was unchanged and CD80 was undetectable even after IFN-gamma treatment. Highly purified CD4+ T cells proliferated in response to IFN-gamma-treated allogeneic HUVEC and MVEC, and this response was efficiently blocked by mAb to MHC class II, ICAM-1 and CD86. Furthermore, the addition of anti-CD86 mAb to the primary culture with allogeneic EC resulted in the induction of alloantigen-specific anergy. These results suggest that CD86 expressed on EC plays a critical role in initiating cellular immune responses to vascularized allografts and would be an important target for immune intervention.

Antibodies, Monoclonal↗