摘要:

The length of time after syngeneic bone marrow re-constitution when tolerance to alloantigens can be induced in adult mice during T cell differentiation from bone marrow cells was studied by exposing those T cells to (recipient × donor)F1spleen cells. Supralethally irradiated C3H/He Slc(C3H; H-2k) mice were reconstituted with 1×107syngeneic T cell-depleted bone marrow cells and then injected intravenously with 5×1107(C3H×C57BL/6[B6])F1(B6C3F1; H-2bxk) or (C3H × AKR/J[AKR])F1(AKC3F1; H-2kxk) spleen cells at various intervals.In the fully allogeneic combination of B6C3F1×C3H, EL-4 tumor originating from B6 was accepted, and survival of grafted B6 skin was significantly prolonged in the tolerant C3H mice treated with irradiation on day −1 followed by injection of syngeneic bone marrow cells on day 0 plus B6C3F1spleen cells on days 0, 5, or 10, in a tolerogen-specific manner. In the multiminor histocompatibility antigen—disparate combination of AKC3F1→C3H, AKR skin grafts were permanently accepted in the tolerant C3H mice treated with AKC3F1spleen cells on days 0, 5, 10, or 15. Immunological parameters, including cytotoxic T lymphocyte activity and delayed foot-pad reaction (DFR), were almost completely suppressed in C3H mice made tolerant of B6 or AKR antigens; A chimeric assay using a direct immu-nofluorescence method revealed that the tolerant C3H mice given B6C3F1spleen cells on day 0 were mixed-chimeric for at least 8 weeks after syngeneic bone marrow reconstitution, but not definitely chimeric thereafter. The C3H mice given AKC3F1spleen cells on day 0 were chimeric even 43 weeks after syngeneic bone marrow reconstitution, but the C3H mice given AKC3F1spleen cells on day 15 showed temporal chimerism that disappeared within 43 weeks. The untolerant mice were never detectably chimeric.These data suggest that the earlier the timing of the injection of F1spleen cells after syngeneic bone marrow reconstitution was, the more profound tolerance was induced. Moreover, the stronger the antigenic disparity between donor and recipient, the earlier the injection of F1spleen cells was required to induce tolerance.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

A 10-day course of cyclosporine treatment inhibits the capacity of DA rats to reject PVG heart grafts and leads to the development of specific unresponsiveness-and indefinite graft survival, which is mediated by a W3/ 25+(CD4+) suppressor cell. In this study the sequential changes in the alloreactivity of the CD4+and CD8+subsets of CsA-treated DA rats were examined. During the induction phase, 8 and 20 days posttransplant, W3/ 25+cells retained normal alloreactivity in that they adoptively restored PVG heart graft rejection in irradiated DA rats. By day 50 they had lost their capacity to restore rejection of PVG grafts but still retained their capacity to effect third party W/F graft rejection. W3/ 25+cells from control grafted rats adoptively restored PVG graft rejection even at 75 days posttransplant, suggesting that the loss of alloreactivity of W3/25+cells in CsA-treated rats was due to the prevention of rejection by CsA, andimot a consequence of sensitization to alloantigen. MRCOX8+cells from CsA-treated rats showed some evidence of sensitization at days 8 and 20 but lost this by day 50. These studies showed that during the induction phase, normal alloreactivity of W3/25+cells is retained and sensitization of MRGOX8+cells occurs. Specific loss of reactivity and suppressor potential of W3/25+cells developed later, when specific un-responsiveness to second donor strain grafts developed in these hosts.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Elimination of CD4+helper T cells by treatment with monoclonal antibodies (mcAb) in vivo has been used as a new mode of immunosuppression in organ transplantation and autoimmune diseases. To explore the potential risks of this therapeutic approach we have studied antiviral responses in mice depleted of CD4+T cells.Depletion of CD4+T cells in vivo completely suppressed the generation of a primary virus-specific cytotoxic response. Injection of high doses of recombinant interleukin-2 (rIL-2) given after virus immunization restored the responsiveness of helper cell—depleted mice to virus-expressing target cells, suggesting a crucial role of IL-2 in antiviral defense mechanisms. In contrast to primary responses, memory cytolytic responses to viral antigens persisted despite depletion of >90% of CD4+helper T cells. The generation of such memory cytotoxic responses was dependent upon help provided by CD4+lymphocytes surviving the antibody therapy. After antibody treatment, frequencies of virus-specific helper cells were minimal in primed mice, excluding insufficient helper cell elimination as the reason for the persistence of memory responses. Data presented here suggest that there exist distinct helper pathways in primary and secondary cytolytic antiviral responses that might represent several subsets of helper T cells as well as differences in helper signals required by distinct effector cells.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Antibody-mediated elimination of CD4+lymphocytes in vivo has been successfully used to suppress the humoral response to foreign antigens and to induce long-term tolerance. However, secondary humoral responses, as well as secondary cytolytic responses specific for viral antigens, could not be prevented, providing evidence for functional heterogeneity within the helper cell compartment. Data presented here support the notion that helper cell requirements for cellular responses to alloantigens are unique and do not involve CD4+T lymphocytes. While the administration of anti-CD4 mcAb failed to suppress allospecific CTL responses, the formation of alloantibodies was initially inhibited in parallel to the deficiency in CD4+helper cells. After regeneration of CD4+T cells, the animals regained the ability to produce specific IgG alloantibodies. The dichotomy of helper pathways in humoral and cellular alloreactive responses challenges the concept of a single CD4+helper cell population. Insights into the functional heterogeneity of helper cells for primary, secondary, and allospecific responses might open new avenues for selective manipulation of helper subpopulations.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Wistar (RT1bv1) rats transplanted orthotopically with ACI (RT1a) livers survive indefinitely without any immunosuppression, while heterotopic heart grafts or skin grafts are rejected acutely in this combination. Levels of alkaline phosphatase after liver allografting remain significantly higher than those found in controls receiving syngeneic grafts. We studied changes in immune responsiveness in rats receiving liver grafts. Local graft-versus-host reactivity was present at all times assayed. Delayed type hypersensitivity reactions were already positive 2 weeks after liver transplantation and increased in strength. Liver graft—bearing rats were subsequently grafted with donor or third-party skin. Third-party skin grafts survived significantly longer on liver-grafted rats than on untreated controls when grafted within the first week after grafting. Donor-type skin grafts survived longer than controls when grafted within the first 4 weeks after liver grafting, although the skin grafts were eventually rejected. Donor-type skin grafted more than 8 weeks after liver grafting was rejected acutely. In an adoptive transfer assay, ACI hearts survived significantly longer in Wistar rats given serum from Wistar donors 2–4 weeks after ACI liver grafts than in untreated controls. On the other hand, spleen cells obtained at any period after liver grafting were not capable of prolonging cardiac allograft survival after transfer to syngeneic recipients. Thus cellular responses to ACI antigen are not changed during the life-span of liver-grafted animals. Evidence suggests that a serum “enhancing” factor protects the donor liver from rejection in the initial period after liver transplantation. The long-term acceptance of liver grafts is discussed.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

In an attempt to study the effects of allogeneic lymphocytes on endothelial cells (EC) and analyze the mechanism whereby such lymphocytes traverse an EC barrier, we have established human microvascular EC monolayers, in vitro, and analyzed the effects of lymphocyte subpopulations on such monolayers. Previous studies have shown that CD16+(natural killer) and CD8+(cytotoxic) lymphocytes but not CD4+(helper) cells bind and induce the appearance of class II major histocompatibility complex antigens on allogeneic EC. The current findings indicate that these same lymphocyte subsets induce marked swirling and elongation of allogeneic EC, and traverse intact EC monolayers. In contrast, none of the functional consequences of the initial lymphocyte-EC adhesion were observed using autologous combinations, despite the presence of significant intercellular binding. Scanning and electron micrographs demonstrate extensive areas of lymphocyte-EC surface contact and EC-coated pit formation, whereas a panel of recombinant cytokines known to alter the surface phenotype of EC fail to induce the same morphologic changes whether used singly or in combination. We postulate that the cellular interactions observed here, in vitro, may represent the initial steps in the rejection of vascularized allografts in vivo.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Intracerebrally (IC) transplanted outbred Wistar and inbred Lewis (AgB1/1) strain rat islets and pancreatic endocrine cells (PEC) were able to function for a prolonged period in nonimmunosuppressed diabetic inbred ACI (AgB4/4) rats across a major histocompatibility barrier. All recipients were sensitized to various degrees to the donor antigens, as demonstrated by circulating cytotoxic antibody, irrespective of the survival of the IC graft. Nevertheless, the antidonor antibody titers in the IC islet and PEC graft recipients were lower and peaked later when compared with ACI recipients that received an intraportal islet allograft. PEC were also transplanted IC in immunized ACI recipients. In recipients hyperimmunized by repeated splenocyte injections, accelerated PEC graft rejection was observed. In recipients with weaker immunization by intraportal whole islet allograft 2 months prior to the IC allograft, the IC PEC allografts were also rejected. To assess if ACI rats with long-term-functioning IC islet/PEC allograft developed tolerance to the donor antigens, these animals were transplanted with a donor-strain skin graft. The skin grafts were all rejected in a first-set fashion similar to normal control ACI rats. Also, 7/12 and 7/9 recipients rejected their functional IC islet or PEC allograft, respectively, following transplantation of a donor-strain skin allograft, thus indicating that the transplanted PEC maintained their antigenicity even after long-term survival of over 1 year in allogeneic recipients. The data indicate that the brain does possess immunoprotective properties for the islet/PEC allograft. The protection, however, is relatively weak and is possibly due to the paucity of the effector mechanism in the brain relative to that normally present systemically.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The influence of antibodies to recombinant murine tumor necrosis factor-alpha (anti—rMuTNF-α) on the development of the graft-versus-host reaction in vivo was investigated. This was done by evaluating the degree of splenomegaly in newborn BDF1(B6×DBA/2) mice 10–11 days after injection of autologous BDF1(controls) or semiallogeneic B6 (test) spleen cells. Splenomegaly, as reflected by the spleen index, among test BDF1mice was 3–4-fold greater than the SI of control BDF1mice. However, the treatment of test BDF1mice with multiple injections of rabbit anti-rMuTNF-α anti-serum resulted in a significant reduction in the SIs. In additional experiments, hamster monoclonal antibodies to rMuTNF-α were also shown to be effective in preventing the GVHR in vivo. Neither normal rabbit serum nor normal hamster IgG affected the GVHR in test BDF1mice. These results indicate that TNF-α plays an important role in the development of the GVHR in vivo and suggest that antibodies, or other antagonists, to TNF-α may have potential use for the management of organ or tissue transplants.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The effect of the graft-versus-host reaction in response to minor histocompatibility antigens on the antibody response to a T-dependent antigen was studied in four strains of mice. Lethally irradiated mice were transplanted with bone marrow plus graded numbers of spleen cells from H-2-compatible donors. Recipients of syngeneic bone marrow transplants and recipients of allogeneic bone marrow depleted of T cells made normal antibody responses to bacteriophage øχ 174 when immunized on day 28 (primary) and day 56 (secondary) after marrow transplantation. Recipients of allogeneic bone marrow plus spleen cells made only small amounts of specific antibody and failed to make IgG antibody after secondary immunization. The pattern of the depressed antibody response suggests that the primary mechanism of immune dysfunction in mice with the minor antigen GVHR is a lack of T helper cell function.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID