摘要:

Anti-CD3 monoclonal antibodies are used clinically to treat organ allograft rejection. Their administration can result in reversal of rejection even in episodes resistant to other modes of therapy. A major limitation to their use has been the humoral response of the patients against the mAbs, resulting in loss of therapeutic efficacy. We have established an animal model for anti-CD3 treatment using the antimurine CD3 mAb, 145–2C11. Exposure of mice to this mAb, like exposure of humans to its antihuman analog OKT3, results in suppression of graft rejection but also stimulates a strong humoral response that abrogates the efficacy of further treatments. Administration of an additional dose of anti-CD3 mAb did not prolong skin graft survival—and, in some instances, resulted in a lethal anaphylactic reaction.In an attempt to suppress the humoral response against the anti-CD3 mAb, anti-CD4 mAb was administered prior to the anti-CD3 mAb treatment. Pretreatment of mice with anti-CD4 mAb (GK1.5) almost completely suppressed the humoral response to anti-CD3 mAb, and permitted readministration of the anti-CD3 mAB without loss of efficacy as assessed by prolongation of skin graft survival. The data suggest that the use of anti-CD4 mAb to suppress the humoral response against anti-CD3 mAb should be attempted clinically, as it might permit repeated courses of anti-CD3 administration, thus significantly improving the efficacy of these agents in the therapy of organ allograft rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

We have examined the ability of highly purified subsets of C57B1/6 L3T4+and Lyt2+cells to cause intestinal graft-versus-host reactions in H-2 mutant mice expressing isolated class I (bm1) or II (bm12) MHC mutations.Heavily irradiated B6×bm12)F1mice given B6 L3T4+T cells (anti—class II GVHR) developed an acute, lethal GVHR that was associated with intense jejunal crypt hyperplasia and an early rise in the density of intraepithelial lymphocytes. Irradiated (B6xbml)F1mice given B6 Lyt2+T cells (anti-class I GVHR) showed a similar phase of crypt hyperplasia within the first 2 weeks, but this was less marked than for anti—class II GVHR and was not associated with an increase in IEL count. Only very minor gut pathology was observed when B6 Lyt2+T cells were transferred to irradiated mice carrying the bm9 class I mutation, which is much weaker than the bm1 mutation and does not stimulate Lyt2+helper T cells. The GVHR mediated by B6 L3T4+and Lyt2+T cells was H-2 class-specific, as no pathology was seen in bm12 recipients of Lyt2+cells or in bml recipients of L3T4+cells.B6 L3T4+and Lyt2+T cells both induced splenomegaly and intestinal GVHR in nonirradiated, 4–5-day-old neonatal (B6×bm12)F, or (B6×bm1)F1mice, respectively, a form of intestinal GVHR that does not require specific cytotoxic T lymphocytes. Again, Lyt2+T cells were less efficient than L3T4+T cells in the induction of GVHR.Thus, both class I and class II MHC-restricted T cells can mediate different forms of intestinal GVHR under appropriate circumstances, but class II MHC-restricted T cells may be more efficient.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Both cyclosporine and bacterial lipopolysaccharide enhance prostanoid synthesis and regulate the immune response. This study was designed to establish whether these agents affect prostanoid synthesis by common or different mechanisms. CsA and LPS stimulate prostanoid synthesis both in human monocytes and smooth muscle cells from guinea pig aorta. Only LPS stimulates synthesis in the presence of exogenous arachidonic acid. Dexamethasone totally blocks CsA but only partially inhibits LPS. CsA and LPS both enhance the release of labeled metabolites from cells labeled with arachidonic acid, but indomethacin only blocks the effect of LPS. CsA and the releasing agent calcium ionophore (A23187) both increase PGE2and PGI2synthesis without changing their relative concentrations, cause the release of free arachidonic acid, and lead to the formation of new metabolites that are not products of cyclooxygenase activity. Preincubation with either CsA or A23187and a subsequent wash deplete the arachidonic acid pool available for prostanoid synthesis. Thus, A23187and CsA have very similar effects on arachidonic acid metabolism. In contrast, LPS increases PGE2and PGI2synthesis and alters their relative concentrations, diminishes the relative concentration of free arachidonic acid, and enhances the formation of new metabolites that are products of cyclooxygenase activity. These differences are explained by mechanisms in which CsA promotes prostanoid synthesis through arachidonic acid release, and LPS promotes prostanoid synthesis through increased cyclooxygenase activity.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Graft failure following transplantation with T cell-depleted bone marrow or with tissue naturally devoid of T cells, such as fetal liver (FL), suggests an important role for T cells in ensuring sustained hematopoietic stem cell engraftment. Whether T cells act by eliminating host residual immune cells—or, alternatively, by helping stem cell growth and differentiation—is still to be determined. The purpose of this study was to analyze the effect of T cell supplementation to the FL graft, using a semiallogeneic murine model where the graft-versus-host reaction is absent. Lethally irradiated C3H/ OuJ mice were grafted with 106FL cells from (C3H/ OuJ×BALB/c) F1hybrid mice, with or without 106isogeneic mature T cells (FL and FL+T groups). Recipient animals were then monitored for survival and for hematologic and immune reconstitution. Eight days postgrafting, the number of multipotent stem cells in the spleen was significantly higher in FL+T as compared with FL recipient mice. Addition of T cells to the FL graft provided a faster recovery of hematological parameters and a significant increase in short-term survival (25.5% 6 weeks of survival in the FL group, as opposed to 55.5% 6 weeks of survival in the FL+T group,P<0.01). By contrast, immunological functions, as assessed by mitogen responses, were quite similar in both groups of animals. Overall a promoting effect of T cells in early stem cell engraftment was clearly demonstrated in this murine model, where GVHR is absent. These results provide in vivo support for a direct T cell effect on hematopoiesis.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The role of recipient hemodilution for postischemic renal medullary red cell trapping was investigated after different periods of cold storage in a conventional cold storage solution (Sacks'). At all cold storage times investigated (4, 12, 24, and 48 hr) medullary red cell trapping was reduced by isovolemic hemodilution, with about 50% reduction of recipient hematocrit. Trapping was also reduced when a modification of a new preservation solution (University of Wisconsin solution [UW]) was used and compared with flush-out and storage in a standard preservation solution (Sacks'). The combination of hemodilution and preservation in modified UW solution had additional capacity to reduce medullary red cell trapping. Thus, even after 48 hr of cold storage, only a moderate trapping was observed. The results also indicate that measurements of medullary red cell trapping offers an accurate method of grading postischemic renal damage.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Our experiments reveal that application of several minor H antigen—disparate skin grafts to adultXenopusover an 18-month period can lead to in vitro generation of CML reactivity toward these minor antigens. Furthermore, we demonstrate that, following MHC-disparate skin graft rejection, adult effectors can efficiently kill both adult and larval donor-strain targets; this killing is MHC-specific and requires MLC restimulation with cells syngeneic to the skin graft donor. The ability to kill larval lymphoblasts, which have been shown elsewhere to be MHC class I-negative but class II-positive, suggests the probable importance of class II—restricted killing in this species.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The maintenance of skin allotolerance induced by perimetamorphic application of MHC-disparate skin to isogeneicXenopusis investigated. Removal of the perimetamorphically applied first-set graft after 4 weeks did not, in general, completely break allotolerance; however, many second-set semi-allogeneic grafts, applied up to 14 weeks after first-set removal, were no longer maintained in perfect condition. Skin allografts tolerated for up to 42 weeks continued to express donor histocompatibility antigens, as indicated by their survival times when transplanted back to the original donor or recipient strain. Treatment with human recombinant IL-2 (rIL-2), shown elsewhere to be an effective immunoregulatory lymphokine forXenopusin vivo, failed to cause long-term-tolerated lst-set allografts, or newlyapplied 2nd-set grafts, to be rejected. In contrast, cyclophosphamide (CyP) treatment led to acute (<4 weeks) destruction of both 1st- and 2nd-set allografts; breaking of tolerance was regularly seen when donor and host differed by two MHC haplotypes, but occurred infrequently in semiallogeneic combinations. The experiments suggest that skin-induced allotolerance is maintained by an immunosuppressive mechanism, that is CyP-sensitive but resistant to rIL-2 treatment.

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

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