UMLS:C0018133 - FACTA Search

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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)

The current studies were designed to evaluated optimal conditions for reduction of graft-versus-host disease (GVHD) by removal of donor T cells from bone marrow inoculum. A model was used in which the addition of spleen cells to donor marrow heavily favored the development of lethal GVHD. Treatment of donor bone marrow plus spleen cells with monoclonal anti-Thy-1.2 antibody plus complement protected lethally irradiated recipients from GVHD across major histocompatibility barriers better than donor cells treated with the same dilution of antibody alone. Engraftment was demonstrated by the presence of high percentages of donor cells in the peripheral blood of these animals and the long-term survival of donor skin grafts. These results may be important in light of the development of new antihuman T cell monoclonal antibodies which may be used in the treatment of donor marrow in clinical transplantation.
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PMID:Bone marrow transplantation across major histocompatibility barriers in mice. Effect of elimination of T cells from donor grafts by treatment with monoclonal Thy-1.2 plus complement or antibody alone. 701 17

Chronic graft-versus-host disease (GVHD) following bone marrow transplantation often gives rise to a severe autoimmune-like state. To investigate the immunopathogenesis of this diseased state, mice receiving a transplant of lymphocytes with major histocompatibility complex (MHC) class II disparity (the simplest model of chronic GVHD) were examined. (B10.Thy-1.1 x B6.C-H-2bm12) F1 mice were injected with parental B10.Thy-1.1 CD4+ splenic T cells. These mice showed intensive lymphocyte infiltration of the target organs, including the liver, salivary glands and pancreas. Indeed, the cell numbers yielded from the spleen and liver were increased, and polyclonal B-cell activation was induced by 14 days after injection. More strikingly, more than 80% of such expanding lymphocytes in the target organs became T cells with T-cell receptors (TCR) of intermediate intensity (i.e. intermediate TCR cells) that carried the properties of extrathymic origin. Despite the homogeneous expansion of intermediate TCR cells in GVHD mice, these T cells were polyclonal in terms of V beta usage. These results, in conjunction with the data using the thymectomized mice as recipients, suggested that extrathymic, intermediate TCR cells possibly of recipient origin might be intimately related to the pathogenesis of the autoimmune-like state resulting from chronic GVHD.
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PMID:Expansion of intermediate T-cell receptor cells in mice with autoimmune-like graft-versus-host disease. 783 36

We compared the findings in the wasting syndrome seen in [MRL lpr/lpr--> MRL +/+] chimeras with those of chronic graft versus host disease (GVHD) in [B10.D2-->BALB/c] chimeras. BALB/c mice were lethally irradiated and administered B10.D2 spleen and bone marrow cells. These mice are identical to MHC and Mls but differ as to genetic background. As a result of chronic GVHD, these [B10.D2-->BALB/c] chimeras showed hair loss, weight loss and atrophy of lymph nodes and spleen beginning 5 weeks after the transplantation. MRL lpr/lpr mice carry the lpr gene and spontaneously develop generalized lymph node swelling and lupus-like autoimmune disease, while congenic MRL +/+ mice lack the lpr gene. The [MRL lpr/lpr-->MRL +/+] chimeras showed wasting and the same symptoms as in [B10.D2-BALB/c] chimeras beginning 16 weeks after cell transfer. Skin biopsy from both chimeras showed very similar changes on HE staining and on immunoperoxidase staining for Ia and Thy-1. Our data suggest that very small differences in minor histocompatibility may induce GVHD which produces severe wasting with lethal consequences. Finally, we succeeded in transferring the wasting syndrome seen in the [MRL lpr/lpr--> MRL +/+] chimera to other MRL +/+ mice by transplanting spleen cells from the [MRL lpr/lpr-->MRL +/+] chimera to lethally irradiated MRL +/+ mice.
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PMID:Comparison of wasting syndrome in [MRL lpr/lpr-->MRL +/+] chimera and graft versus host disease in [B10.D2-->BALB/c] chimera and an attempt to transfer the wasting syndrome in [MRL lpr/lpr-->MRL +/+] to MRL +/+ mice. 791 43

When MRL/Mp- +/+ (MRL/+) mice are lethally irradiated and then reconstituted with MRL/Mp-lpr/lpr (MRL/lpr) spleen and/or bone marrow cells (BMCs), the mice develop a graft-versus-host disease (GVHD)-like syndrome which is known as lpr-GVHD. We analyzed lpr-GVHD by adoptive transfer experiments using congenic MRL/lpr-Thy-1.1 mice to distinguish the donor and recipient cells. MRL/+ mice were lethally (9.5 Gy) irradiated and then reconstituted with BMCs of MRL/lpr-Thy-1.1 mice treated with anti-Thy-1.1 monoclonal antibody (mAb) plus complement (C). The mice were sacrificed 5 to 6 weeks after bone marrow transplantation (BMT), and the spleen cells were transferred to second recipients. The second recipients (MRL/+ or MRL/lpr mice) were non-irradiated, sublethally (6 Gy) irradiated or lethally (9.5 Gy) irradiated. The lethally irradiated mice were also injected with syngeneic BMCs treated with anti-Thy-1.2 mAb plus C. When whole spleen cells (1 x 10(8) were injected into lethally irradiated MRL/+ mice, the mice showed short survival (1.2-1.5 months) and severe histological changes in the spleen (atrophy and fibrosis), liver (lymphoid infiltration in the Glisson's sheath) and lung (lymphoid infiltration around the bronchus and vessel). The sublethally irradiated MRL/+ mice at 2 months after transfer showed histological changes similar to the lethally irradiated MRL/+ recipients, although the former survived more than 3 months, suggesting that histological changes do not reflect on mortality. These GVH-like diseases were not transferable to MRL/lpr mice; they developed autoimmune diseases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Analyses of lpr-GVHD by adoptive transfer experiments using MRL/lpr-Thy-1.1 congenic mice. 794 6

Antibodies against T cells are widely used as immunosuppressive agents in clinical therapy. As effector functions of chimeric or humanized anti-T cell antibodies cannot be predicted in vitro, we compared T cell-depleting effects of human isotypes in vivo with their immunosuppressive consequences in a mouse BMT model. This system is based on chimeric antibodies with a mouse pan T cell specificity and human constant regions. To secure optimal immunosuppression, the specificity for Thy-1.2--one of the best-characterized T cell antigens--was selected, as Thy-1.2-specific antibodies prevent graft-versus-host disease in fully mismatched mice. Chimeric mouse anti-Thy-1.2 antibody with the human IgG1 Fc part was found to be equally effective in preventing graft-versus-host disease mortality as the highly protective anti-Thy-1.2 mouse IgG2a isotype, while human IgG3 was far less effective. This was not predictable by measuring the degree of T cell depletion in peripheral blood. T cell depletion in lymph nodes, however, exactly reflected the results obtained in the BMT system. In addition, this system offers the advantage of assessing the influence of reduced antigen density by using heterozygous Thy-1.2 mice.
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PMID:A mouse model for the preclinical evaluation of immunosuppressive effector functions of human isotypes. The human IgG1 isotype is superior to IgG3. 810 76

Lethal GVHD in the fully allogeneic BALB/c (donor)-(C57BL x CBA)F1 (recipient) mouse strain combination could be prevented by a single dose of IgG2b monoclonal antibodies (moAb) directed to T cells. The influence of the time of administration of this moAb after GVHD induction and the effect of anti-T cell subset moAb on the development of GVHD was investigated in this study. Moreover, the state of tolerance in the mice that had become long-term chimeras was examined. Anti-Thy-1 treatment of the recipients 1 day before, 2 h before or 1 day after reconstitution almost completely prevented lethal GVHD. A single dose of 100 micrograms of anti-Thy-1 was as effective as four daily doses of 25 micrograms each. Treatment with a single dose of 25 micrograms or with intervals of 4 days between doses of 25 micrograms was statistically significantly less effective. We injected the recipients with moAb directed to the CD4+ or CD8+ T cells subsets. Using a dose of 100 micrograms moAb, anti-CD4 treatment appeared to be less effective than anti-Thy-1 treatment whereas anti-CD8 treatment was not effective at all. A double dose of anti-CD4 was equally effective as anti-Thy-1 treatment. All mice that became long term survivors remained free of signs of GVHD and were > 99% repopulated with donor type cells. Injection of spleen cells from these BALB/c into (C57BL x CBA)F1 chimeric mice was used to reconstitute lethally irradiated BALB/c, BALB.K and (C57BL x CBA)F1 recipients. Lethal GVHD developed in the BALB.K and (C57BL x CBA)F1 recipients but not in the BALB/c recipients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prevention of lethal graft-versus-host disease in mice by monoclonal antibodies directed against T cells or their subsets. I. Evidence for the induction of a state of tolerance based on suppression. 819 71

Graft-versus-host disease (GVHD) is known to cause profound dysregulation of the immune system, although its effector mechanisms are not fully understood. In this study, we investigated what factors influenced the development of GVHD. BALB/c nude mice (H-2d) injected with MHC-disparate B6(H-2b) spleen cells exhibited transient GVHD such as hunched back, diarrhea, loss of body weight and splenomegaly. No animals died during the period of observation. BALB/c nude mice produced alloantibodies to the donor cells. The injection of the serum from GVHD nude mice into naive nude mice can protect from GVHD. Donor derived H-2b+ cells were recognized in the recipient lymph nodes and skin. Prevention of GVHD was achieved by the pretreatment of spleen cells with anti-Thy-1.2 antibody or anti-CD4 antibody and complement, while it was not done by the pretreatment of spleen cells with anti-CD8 antibody and complement. These data demonstrate that Thy-1.2+ CD4+ CD8- lymphocytes are important effector cells and alloantibodies to the donor cells prevent GVHD in this model.
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PMID:Studies on transient graft-versus-host disease in BALB/c nude mice injected with allogeneic C57BL/6 splenocytes. 886 71

Despite improved procedures in chemotherapy and bone marrow transplantation (BMT), post-BMT leukemia relapse rates have remained rather constant in the last decade. Immunotherapy with monoclonal or bispecific antibodies (bsAb) is a promising approach to improve this situation, but is hampered by the absence of tumor-specific antigens on the majority of tumors. To evade this problem, we developed a new tumor-specific approach in which bispecific antibodies exploit chimerism after allogeneic BMT by redirecting donor T cells against recipient-specific antigens on tumor cells. Two different leukemia relapse models were established using a T-cell lymphoma (ST-1) and a B-cell lymphoma (BCL1) to evaluate the efficiency of such a therapy. In these experiments, irradiated BALB/c (Thy-1.2+, I-Ad) mice were transplanted with C57BL/6 Thy-1.1 (I-Ab) BM cells under the protection of graft-versus-host disease-preventing monoclonal antibodies. Forty-five days after BMT, the chimeric mice were injected with either 2 x 10(4) recipient-type, Thy-1.2+, CD3- ST-1 cells or major histocompatability complex (MHC) class II+ (I-Ad)-BCL1 cells. Four days later, the mice were treated with 8 microg bsAb G2 (anti-CD3 x anti-Thy-1.2) or 10 microg (+10 microg, day 6) bsAb BiC (anti-CD3 x anti-I-Ad), respectively. These combinations guaranteed exclusive binding of the bsAbs target arms to tumor cells, leaving the surrounding, donor-type hematopoietic cells unbound. Compared with the parental antibodies, the bsAbs markedly reduced tumor mortality. Between 34% and 83% of mice survived in the bsAb groups compared with 0% of the control groups treated with parental antibodies, clearly documenting the benefit of the redirection principle. Furthermore, cytokine release (interleukin-6) after anti-CD3 antibody or bsAb treatment was decreased by administering a low-dose antibody preinjection. We have shown (1) that 6 weeks after BMT, when donor T-cell reconstitution is still in progress, T-cell-redirecting bsAb are clearly superior to parental antibodies in terms of tumor cell elimination; and (2) that the polymorphism of a common antigen such as Thy-1 or a clinically more relevant target antigen such as MHC class II can be used as an operational tumor-specific antigen after allogeneic BMT.
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PMID:Bispecific antibodies target operationally tumor-specific antigens in two leukemia relapse models. 897 58

Counterflow centrifugal elutriation (CCE) has been a highly efficient physical method for separating T cells from bone marrow (BM) without impairing cell function and yield. To investigate the usefulness of CCE, the hematopoietic potential as well as the level of T cell contamination in rotor-off (R/O) fraction of BM was studied using a murine bone marrow transplantation (BMT) model [C3H/He (H-2k)-->BALB/C (H-2d)]. The total recovery of cells after CCE procedure was 71.4%. Morphologically, R/O fraction contained abundant mononuclear cells and a few lymphocytes. The numbers of colony forming unit for granulocyte/monocyte (CFU-GM), Sca-1+ cells, and T cells were compared among four fractions of CCE (fractions at flow rate of 17, 25, 28 mL/min, and R/O fraction). The number of CFU-GM per 10(5) nucleated cells in each fraction were significantly higher in R/O fraction (331.3 +/- 34.4) compared to unfractionated marrow (UM) (21.1 +/- 1.3) and fraction of 17 mL/min (FR 17) (23.7 +/- 2.2 ) (chi2 = 0.0044). Neither fraction of 25 mL/min (FR 25) nor fraction of 28 mL/min (FR 28) contained CFU-GM colonies. The concentration of Sca-1+ cells in R/O fraction was significantly higher (1.96-fold) than UM (p < 0.05), and 80.0 +/- 10.1% of Sca-1+ cells in UM were recovered in R/O fraction; 88.1% of Thy-1.2+ T cells were eliminated in R/O fraction (p < 0.05). Mice receiving UM after lethal irradiation (875cGy) suffered from severe graft-versus-host disease (GVHD) and all five died within 7 days after BMT procedure (Group A). Of interest, mice receiving mixture of R/O fraction with lymphocyte-rich fraction (FR 25 plus FR 28) to equalize T cell number as UM, developed severe GVHD and four out of five died (probability of survival; 20%) (Group B). Mice receiving R/O fraction had mild GVHD and four out of five survived for at least 90 days (probability of survival; 80%) (Group C). In group C, probability of survival (p = 0.0006) was higher, and severity of GVHD (p = 0.0043) and progression rate of GVHD (p = 0.02) was lower. In conclusion, the elutriated R/O fraction cells of BM have the advantages of stable engraftment and tolerable GVHD in murine allogeneic BMT with complete major histocompatibility disparity. This could be directly applicable to patients with high risk of GVHD and graft failure in upcoming clinical trials.
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PMID:Effectiveness of rotor off fraction in allogeneic murine bone marrow transplantation with complete disparity of major histocompatibility. 1039 Jan 98

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