Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With a model in which CBA T cells cause lethal graft-versus-host disease (GVHD) in irradiated B10.BR mice (H-2-compatible mice that express multiple minor histocompatibility antigen [HA] differences), information was sought on whether the induction phase of GVHD to minor HA is H-2 restricted. When unprimed CBA (H-2k) T cells were recirculated from blood to lymph for 1 d through irradiated H-2-compatible B10.BR or B10.K mice, the T cells underwent specific negative selection to the minor HA of the host, i.e, the filtered T cells failed to cause GVHD after transfer to B10.BR mice. With filtration through totally H-2-different B10 (H-2b), B10.D2 (H-2d), or B10.S (H-2s) mice, by contrast, no selection occurred, i.e., the filtered cells were unimpaired in their capacity to kill B10.BR mice. Selection was marked after filtration through H-2-semiallogeneic (B10 X CBA)F1 mice. These data, together with the results of filtering T cells through various H-2 recombinant strains, indicated that selection depended upon the donor and filtration host sharing determinants encoded by both the K- and D-ends of the H-2 complex. Compatibility only in the I region failed to cause demonstrable selection.
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PMID:Negative selection of T cells causing lethal graft-versus-host disease across minor histocompatibility barriers. Role of the H-2 complex. 696 18

Conditions for preparations of cells used in immunogenetic studies may substantially affect their properties and the results obtained. It was found that short-term incubation or a mere preparation of parental spleen cells in a medium containing either xenogeneic serum or concanavalin A (Con A) increase their ability (after footpad injection) to induce enlargement of the popliteal lymph node in (B10.LP x A/Ph)F1 hybrid recipients. Under similar conditions, enlargement of PLN could be induced also by syngenetic F1 hybrid cells. The greater lymphadenomegaly following the injection of parental or syngeneic cells prepared in serum-containing medium may be explained by the host reaction against additional foreign antigens rather than increased GVH reactivity or autoimmunity.
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PMID:Addition of serum to the medium used for preparation of cell suspensions as a possible source of artifacts in cell-mediated reactions studied by means of the popliteal lymph node test. 724 Jul 66

A new pharmacologic agent, anti-CD3F(ab')2-ricin toxin A chain (RTA), was synthesized for the purpose of targeting T cells and as a means of treating established graft-versus-host disease (GVHD). The Fc region of anti-CD3 monoclonal antibody (MoAb) was removed to prevent its ability to activate T cells. The resulting F(ab')2 fragments were conjugated to deglycosylated RTA (dgRTA), a catalytic and potent phytotoxin. The resulting immunotoxin (IT) was potent (greater than 95% inhibition) and selective in inhibiting T-cell mitogenesis in vitro. In vivo, the IT depleted 80% of T cells in mice receiving bone marrow (BM) transplants. Transplantation in an aggressive acute GVHD model using C57BL/6 donor cells and H-2 disparate B10.BR recipients resulted in an infiltration of CD3-expressing cells and a median survival time (MST) of 20 to 30 days. A 5-day course of anti-CD3F(ab')2-RTA (30 micrograms/d intraperitoneally) beginning 7 days after GVHD induction was beneficial in treating established GVHD in these mice, as evidenced by significantly prolonged survival (MST, greater than 80 days), superior mean weight values, and improved clinical appearance. Neither intact anti-CD3, unconjugated anti-CD3 F(ab')2 fragments, nor a mixture of anti-CD4 and anti-CD8 MoAbs (which are highly effective in prophylactic models) were as effective. F(ab')2 fragments made from anti-Lyt-1 (the murine homologue of human anti-CD5) linked to RTA were also not effective, despite the fact that both anti-CD3F(ab')2-RTA and anti-Lyt-1F(ab')2-RTA had similar half-lives of about 9 hours. The IT also increased MST in two aggressive models of GVHD across non-H-2 minor histocompatibility barriers, indicating that the usefulness of anti-CD3F(ab')2-dgRTA is not limited to a single-strain combination. This agent should be further investigated as an alternative to current strategies for treating steroid refractory GVHD.
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PMID:Therapy for ongoing graft-versus-host disease induced across the major or minor histocompatibility barrier in mice with anti-CD3F(ab')2-ricin toxin A chain immunotoxin. 749 98

We tested whether the in vivo infusion of recombinant, soluble CTLA4 fused with Ig heavy chains, as a surrogate ligand used to block CD28/CTLA4 T-cell costimulation, could prevent efficient T-cell activation and thereby reduce graft-versus-host disease (GVHD). Lethally irradiated B10.BR recipients of major histocompatibility complex disparate C57BL/6 donor grafts received intraperitoneal injections of human CTLA4-Ig (hCTLA4-Ig) or murine CTLA4-Ig (mCTLA4-Ig) in various doses and schedules beginning on day -1 or day 0 of bone marrow transplantation (BMT). In all five experiments, recipients of CTLA4-Ig had a significantly higher actuarial survival rate compared to mice injected with an irrelevant antibody control (L6) or saline alone. Survival rates in recipients of hL6 or PBS were 0% at 29 to 45 days post-BMT. In recipients of CTLA4-Ig, survival rates were as high as 63% mice surviving 3 months post-BMT. However, protection was somewhat variable and recipients of CTLA4-Ig were not GVHD-free by body weight, clinical appearance, and histopathologic examination. There were no significant differences in the survival rates in comparing injection dose, injection duration, or species of CTLA4-Ig (hCTLA4-Ig v mCTLA4-Ig). Splenic and peripheral blood flow cytometry studies of long-term hCTLA4-Ig-injected survivors showed a significant peripheral B-cell and CD4+ T-cell lymphopenia, consistent with GVHD. A kinetic study of splenic reconstitution was performed in mice that received hCTLA4-Ig and showed that mature splenic localized CD8+ T-cell repopulation was not significantly different in recipients of hCTLA4-Ig compared with hL6, despite the significant increase in actuarial survival rate in that experiment. These data suggest that the beneficial effect of hCTLA4-Ig on survival is not mediated by interfering with mature donor-derived T-cell repopulation post-BMT. Neither hCTLA4-Ig nor mCTLA4-Ig interfered with hematopoietic recovery post-BMT. We conclude that CTLA4-Ig (most likely in combination with other agents) may represent an important new modality for GVHD prevention.
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PMID:In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice. 751 23

Studies were designed to prospectively evaluate the effects of selective depletion for donor T cells strongly expressing the CD3 and CD5 pan-T antigens on the incidence of leukemia relapse following bone marrow transplantation. This evaluation was performed under controlled conditions in a mouse model for MHC-matched unrelated-donor transplantation, employing Rauscher leukemic SJL/J mice as the recipients and leukemia-resistant B10.S mice as the donors. Selective donor cell depletion for CD3 and CD5 was accomplished ex vivo prior to transplantation by incubation with the appropriate monoclonal antibody plus complement. When untreated, Rauscher leukemia resulted in a 97% fatality incidence. This was reduced to 30% by the transplant of non-depleted B10.S cells, with another 37% recipients dying from GVHD and graft failure. CD3 depletion reduced the GVHd deaths to 6% but increased relapse to 62%. Conversely, CD5 depletion had no effect on relapse or on GVHD but did significantly increase graft failure, thus negatively affecting survival. Evaluation of the results, done in conjunction with flow cytometry analysis of the effects of CD3 versus CD5 depletion on the donor cells, suggests that the T cells involved in suppressing leukemic relapse in these studies, and hence contributing to the GVL response, most probably had a phenotype of CD3+, CD5-.
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PMID:Comparison of the effects of CD3 and CD5 donor T cell depletion on graft-versus-leukemia in a murine model for MHC-matched unrelated-donor transplantation. 751 54

The pathophysiologic role of nitric oxide (NO) in graft-versus-host disease (GVHD) was investigated in a murine bone marrow (BM) transplantation model where donor and recipient were H-2-matched but differed at multiple minor histocompatibility antigens. Host AKR/J (H-2K) mice received lethal total body irradiation as pretransplant conditioning followed by transplantation of donor B10.BR (H-2K) BM cells with or without spleen cells as a source of GVH-reactive T cells. NO production, as assessed by serum nitrate and nitrite levels, was increased for up to 3 weeks posttransplant in animals undergoing both moderate and severe GVHD. Administration of NG-methyl-L-arginine (L-NMA), an inhibitor of nitric oxide synthase, to animals undergoing GVHD resulted in effective suppression of NO production when compared with saline-treated GVHD control animals. Suppression of NO production by L-NMA in GVHD animals was associated with enhanced weight loss early posttransplant and decreased overall survival. Histologic analysis of tissues from L-NMA-treated and saline-treated GVHD animals showed that early weight loss was not because of an exacerbation of GVHD, indicating that NO did not appear to play an immunosuppressive role in this experimental model. L-NMA-treated animals with enhanced weight loss were observed to have splenic atrophy, decreased extramedullary hematopoiesis, and a reduction in BM cellularity when compared with GVHD control mice that were weight-matched before transplant. Analysis of T-cell chimerism in the spleen showed that L-NMA treatment impaired donor T-cell repopulation. In vitro colony-forming unit (CFU) assays were performed to further assess the role of NO on BM progenitor cell growth. L-NMA added directly into culture had no effect on CFU-granulocyte/macrophage (CFU-GM) formation in normal murine BM. In contrast, total CFU-GM from L-NMA-treated animals were significantly reduced when compared with GVHD controls or BM control animals who did not develop GVHD. Collectively, these data indicate that inhibition of NO impairs hematopoietic reconstitution and support the premise that NO appears to play a novel role in the facilitation of alloengraftment posttransplant.
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PMID:Inhibition of nitric oxide production is associated with enhanced weight loss, decreased survival, and impaired alloengraftment in mice undergoing graft-versus-host disease after bone marrow transplantation. 752 27

Studies were undertaken to determine whether the doses of FK506 that are effective for acute GVHD prophylaxis following lethal irradiation and bone marrow transplantation (BMT) would also suppress myeloid cell reconstitution. FK506 (3 mg/kg/day) abrogated acute lethal graft versus host disease (GVHD) in lethally irradiated C57BL/10SnJ (H-2b) recipient mice given histoincompatible BM plus spleen cells from B10.BR (H-2k) donors and this dose was used in all of the studies. Endogenous and exogenous myeloid repopulation was studied in mice given daily injections of either FK506, an equivalent amount of carrier solvent or no treatment throughout the interval between total body irradiation (TBI) and the day of assay. Repopulation was studied after 400 or 500 cGy TBI (endogenous) and after 950 cGy TBI plus injection with syngeneic BM (exogenous). No consistent adverse effects of FK506 were seen during either exogenous or endogenous recovery. Parameters studied included hematocrit (Hct), WBC count, cells per humerus, spleen weight, splenic colony-forming units, % spleen or BM 59Fe uptake and colony forming cells per humerus. Similarly, when lethally irradiated secondary recipients were reconstituted with BM from FK506 treated primary recipients (lethal irradiation plus exogenous BM), no consistent effects were observed. These data suggest that FK506 given to prevent GVHD would not compromise the myeloid recovery that is critical for survival in the interval of time following shortly after BMT.
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PMID:Short-term myeloid reconstitution following TBI is not adversely affected by doses of FK506 that abrogate lethal GVHD. 752 89

We have developed an in vitro system in which C57BL/6 donor splenocytes are exposed to B10.BR host alloantigens in the context of deficient CD28:B7 signaling as a means of preventing graft-versus-host disease (GVHD). Although 54% to 82% of MLR alloresponse was inhibited by cytotoxic T-lymphocyte antigen 4 (CTLA4)-Ig treatment of host stimulator cells, treated splenocytes were still capable of causing GVHD when infused in vivo. By adding anti-leukocyte function antigen 1 (anti-LFA1) antibody to hCTLA4-Ig in vitro to coblock the LFA1:intercellular adhesion molecule (ICAM) signaling, splenic alloresponse was inhibited by > or = 89%, yet GVHD induction capabilities were retained. Because antigen-primed cells might be more susceptible to CD28:B7 blockade, we investigated whether hCTLA4-Ig alone, anti-LFA1 antibody alone, or the combination of both added to donor-antihost in vitro primed cells could reduce GVHD. To facilitate hyporesponsiveness induction and to block B7 and ICAM ligands that are upregulated during GVHD, these reagents were also administered to recipients post-BMT. We have shown that hCTLA4-Ig plus anti-LFA1 antibody is highly effective in preventing GVHD-induced lethality (88% to 100% of treated mice surviving versus 0% to 28% of controls surviving). For optimal prevention, both hCTLA4-Ig and anti-LFA1 must be used in vitro in the context of donor-antihost primed splenocytes and continued in vivo. This in vitro-in vivo combined approach was associated with donor engraftment, and recipients were not globally immunosuppressed. We conclude that blocking both the CD28/B7 and the LFA1:ICAM pathways are critical to effective GVHD prevention and may offer advantages to in vitro donor T-cell removal.
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PMID:Coblockade of the LFA1:ICAM and CD28/CTLA4:B7 pathways is a highly effective means of preventing acute lethal graft-versus-host disease induced by fully major histocompatibility complex-disparate donor grafts. 753 22

We previously reported that Mls-1a B10.D2 donor preimmunization prevents the development of a lethal graft-versus-host disease (GVHD) directed against host minor histocompatibility antigens (mHAgs) in lethally irradiated (DBA/2 x B10.D2)F1 recipients (LS mice). In the same combination, the graft of T-depleted bone marrow cells also results in no GVHD (TCD BM mice). Both groups of mice exhibit a host specific tolerance. In this paper, we examined whether a graft-versus-leukemia (GVL) effect can still take place without lethal GVHD in LS and TCD BM mice. The i.v. injection of P815 tumor cells into these mice, 2-3 months after the graft, indicates an antitumor activity in LS mice but not in TCD BM mice. When the P815 cells were administered 1 day before irradiation and graft, the leukemic mortality was significantly delayed in mice reconstituted with BM and spleen cells from a preimmunized donor, but not in mice reconstituted with T cell-depleted BM. In LS mice, a subclinical GVHD develops, probably due to CTL alloreactivity against host mHAgs that is observed in vitro. Moreover, cell depletion of the donor inoculum before grafting indicates that the antitumor effect is exclusively mediated by CD8+ T cells. In summary, a beneficial GVL effect, mediated by CD8+ T cells, can be preserved without lethal GVHD.
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PMID:Peripheral tolerance to host minor histocompatibility antigens in radiation bone marrow chimeras abrogates lethal GVHD while preserving GVL effect. 758 Nov 9

Murine GVHD across multiple minor histocompatibility barriers (B10.D2 into irradiated BALB/c) results in cell-mediated destruction of bile ducts inside the liver. Similar changes are characteristic of hepatic GVHD in humans following BMT. We have defined the phenotypes of inflammatory cells and the accessory/adhesion molecules expressed in the liver between day 7-14 of murine GVHD. T cells (CD3+) comprised 65% of hepatic inflammatory cells. alpha-beta and gamma-delta cells accounted for 92 and 8%, respectively of hepatic T cells. The percentage of CD4+ cells (29%) was 3 times that of CD8+ cells (11%). Lymphocyte function-associated antigen-1 (LFA-1) was expressed by the majority of inflammatory cells. Thirty per cent of the cells were positive for Mac-1, a differentiation marker of macrophages, large granular lymphocytes, and natural killer cells. Expression of intercellular adhesion molecule-1 and major histocompatibility complex class II (IAd) molecules on bile duct epithelial and portal vein endothelial cells was induced during GVHD. These results suggest that hepatic GVHD is induced by donor alpha-beta T cells through mechanisms that may involve CD4:1Ad and LFA-1:ICAM-1 interactions.
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PMID:Liver T cell subsets and adhesion molecules in murine graft-versus-host disease. 758 Nov 14


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