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)

We have studied graft-versus-host disease (GVHD) after transplantation of allogeneic peripheral blood stem cells (PBSC) mobilized by either recombinant canine granulocyte colony-stimulating factor (rcG-CSF) alone or combined with stem cell factor (rcSCF). These studies were prompted by the observation of extremely rapid and sustained engraftment of growth factor-mobilized PBSC in the autologous setting using genetically marked cells and changes in function of T lymphocytes from donors that had undergone mobilization. Specifically, lymphocytes from growth factor-treated donors were hyporesponsive in mixed leukocyte culture and in response to Con A, raising hopes that GVHD in dogs given growth factor mobilized allogenic PBSC might be altered in a beneficial way. Eighteen dogs were given a median of 17.1 x 10(8) PBSC/kg from littermate donors after 920 cGy of total body irradiation without postgrafting immunosuppression. Donors were either genotypically DLA-identical (n = 9) or DLA-haploidentical (n = 9). The median number of colony-forming unit-granulocyte macrophage (CFU-GM) infused was 27 x 10(4)/kg, and the number of CD34+ cells in the transplant was on the order of 4.6 x 10(6)/kg. The dogs received a median of 52.8 x 10(7) CD4 cells/kg and 13.7 X 10(7) CD8 cells/kg. All 18 dogs had prompt hematopoietic engraftment of donor cells as assessed by chimerism studies using variable number tandem repeat, as well as cytogenetic markers. Three of the nine dogs given grafts from DLA-identical littermates had fatal GVHD, five had transient GVHD, and one had no GVHD. All nine DLA-haploidentical recipients of PBSC developed fatal hyperacute GVHD. In conclusion, the expectation about rapid engraftment was fulfilled. However, incidence and severity of acute GVHD after transplantation of mobilized PBSC were not different than previously reported for nonmobilized PBSC or marrow. This model will allow for further studies, including T-cell depletion to minimize GVHD without increasing graft rejection.
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PMID:Allogeneic transplant of canine peripheral blood stem cells mobilized by recombinant canine hematopoietic growth factors. 860 71

Intravenous immune globulin (IVIG) exhibits a number of immunomodulatory properties that are mediated by the Fe portion of IgG and by the spectrum of variable (V) regions contained in the immune globulin preparations. Five predominant and non-exclusive mechanisms of action have been proposed to account for the immunomodulatory effects of IVIG in immune-mediated diseases: (i) functional blockade of Fc receptors on splenic macrophages; (ii) inhibition of complement-mediated damage, an effect that is dependent on the ability of IgG to bind C3b and C4b and thus reduce the number of activated complement fragments that may deposit on target surfaces of complement activation; (iii) modulation of the production of cytokines and cytokine antagonists; (iv) neutralization of circulating autoantibodies by complementary (e.g. anti-idiotypic) antibodies in IVIG, a mechanism that accounts for the rapid decrease in titre of circulating autoantibodies that is often observed within hours following the infusion of IVIG; (v) selection of immune repertoires, a complex set of effects that may be observed in individuals receiving IVIG far beyond the half-life of the infused immunoglobulin and that is directly relevant to the ability of IVIG to, for example, suppress autoantibody-producing clones in patients with antibody-mediated autoimmune disease and modulate graft versus host disease (GVHD). IVIG has been shown to downregulate or activate B-cell clones expressing surface IgG that is complementary (anti-idiotypic) to V regions of antibodies present in IVIG. IVIG has been shown also to interact with surface molecules of T cells that are essential to immune regulation, such as the alpha beta TCR, CD5, CD4, non-polymorphic determinants of MHC class I molecules and adhesion molecules of T and B cells. The complex interactions of IVIG with functional molecules of cells of the immune system are relevant to its therapeutic effects in T cell- as well as B cell-mediated diseases and indeed, to our understanding of the physiological role of normal IgG and antibody networks in controlling autoreactivity in healthy individuals.
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PMID:Mechanisms of action of intravenous immune globulin in immune-mediated diseases. 862 40

We prospectively studied immune reconstitution in 102 children who underwent T-lymphocyte depleted bone marrow transplants using either closely matched unrelated donors or partially matched familial donors by assaying total lymphocyte counts (TLC), T-cell subsets, B cells, and natural killer cells. TLC, CD3+, and CD4+ T-cell counts remained depressed until 2 to 3 years posttransplant, whereas CD8+ T-cell counts normalized by 18 months, resulting in an inverted CD4:CD8 ratio until 12 months posttransplant. Although the percentage of NK cells was elevated early posttransplant, their absolute numbers remained normal. CD20+ B cells were depressed until 12 to 18 months posttransplant. Factors affecting immunophenotypic recovery were analyzed by nonparametric statistics. Younger patients tended to have higher TLC posttransplant. Higher marrow cell doses were not associated with hastened immunophenotypic recovery. Graft-versus-host disease (GVHD) and/or its treatment significantly delayed the immune reconstitution of CD3+, CD4+, and CD20+ cells. The presence of cytomegalovirus was associated with increased CD8+ counts and a decrease in the percentages of CD4+ and CD20+ cells.
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PMID:Reconstruction of the immune system after unrelated or partially matched T-cell-depleted bone marrow transplantation in children: immunophenotypic analysis and factors affecting the speed of recovery. 870 19

Clinical trials and experimental studies have demonstrated that donor T cells can play a critical role in preventing allogeneic marrow graft rejection. Results of a previous study showed that donor T cells were most effective for preventing rejection when they recognize an alloantigen expressed by recipient T cells and can cause graft-versus-host disease (GVHD). The present study examined models where marrow graft rejection can be prevented by donor T cells that do not recognize host alloantigens and cannot cause GVHD. Donor T cells prevented rejection of major histocompatibility complex (MHC) class I and II-disparate F1 marrow in parental recipients prepared with > or = 800 cGy total body irradiation (TBI) but not in those prepared with < or = 750 cGy TBI. In recipients prepared with high TBI exposures, rejection was mediated entirely by host CD8 cells. With lower TBI exposures, rejection was mediated by host CD4 cells and CD8 cells. These observations suggested the hypothesis that donor T cells prevent rejection mediated by host effectors that recognize donor MHC class I alloantigens but do not prevent rejection mediated by host effectors that recognize donor class II alloantigens. Consistent with this hypothesis, further experiments showed that F1 donor T cells can prevent rejection of MHC class I-disparate marrow in irradiated parental recipients but have no detectable effect on rejection of MHC class II-disparate marrow. We propose that the expression of MHC class I molecules on donor T cells makes it possible for these cells to inactivate the host response against donor class I alloantigens through a veto mechanism, whereas the absence of MHC class II molecules on murine T cells explains why these cells cannot inactivate the host response against donor class II alloantigens. Finally, donor CD4 cells and CD8 cells were equivalently effective for preventing rejection of F1 marrow in parental recipients, suggesting that veto activity is not restricted solely to the CD8 subset of murine T cells. A veto mechanism could enable donor T cells to prevent allogeneic marrow graft rejection without causing GVHD.
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PMID:Prevention of allogeneic marrow graft rejection by donor T cells that do not recognize recipient alloantigens: potential role of a veto mechanism. 870 55

To determine if partial T cell depletion and intensive post-transplant immunosuppression is effective for the prevention of graft-versus-host disease (GVHD) in pediatric recipients of HLA-non-identical marrow transplants, 10 children with leukemia received high-dose thiotepa, cyclophosphamide and total body irradiation followed by transplantation of CD3-depleted marrow from matched unrelated or one-antigen mismatched related adult donors. To maximize the number of stem cells infused, a large volume (1-1.51) of marrow was harvested from the donors. After immunopurging, the marrow infused contained a median of 3.7 x 10(6) CD34+ cells/kg, 1.4 x 10(6) CD3+ cells/kg, and 1.6 x 10(6) CD5+ cells/kg as assessed by flow cytometry. Cyclosporine, methylprednisolone and anti-CD4 ricin A chain immunotoxin (XZ-CD5) were used for prevention of GVHD post-transplant. All patients achieved an ANC > 0.5 x 10(9)/l. No patient developed capillary leak syndrome or renal failure from XZ-CD5. Five developed grade 2-4 acute GVHD, and all responded to treatment with steroids. Five of nine evaluable patients developed chronic GVHD. Two patients relapsed, but the most common cause of death was infection with or without chronic GVHD. Four patients survive 10+ to 27+ months post-transplant. XZ-CD5 is well-tolerated in T cell-depleted marrow transplant recipients. However, partial T cell depletion and intensive post-transplant immunosuppression did not prevent moderate acute GVHD or chronic GVHD. This may have been due to the high number of T cells infused with the marrow.
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PMID:Prevention of graft-versus-host disease with anti-CD5 ricin A chain immunotoxin after CD3-depleted HLA-nonidentical marrow transplantation in pediatric leukemia patients. 875 Feb 62

The occurrence of graft-versus-host disease (GvHD) following small bowel transplantation (SBTx) can be tuned by the recipient's initial natural killer (NK) cell activity, which modifies the immunogeneic balance between donor and host immunocompetent cells. This study was aimed to investigate the role of host NK cells on the incidence and severity of GvHD following SBTx. Intraperitoneal administration of 50 microl ascites fluid of the highly specific anti-NKR-P1 monoclonal antibody (mAb) 3.2.3 into F1 recipient animals on three consecutive days prior to SBTx was performed to suppress NK activity in F1 hybrids. In vivo treatment with 3.2.3 mAb effectively depleted recipient NK activity for at least 10 days in spleens and mesenteric lymph nodes of F1 hosts. In contrast to nontreated F1 recipients, all 3.2.3 mAb-pretreated F1 animals suffered from severe signs of GvHD, and the mean survival time was decreased significantly from 16.0 +/- 0.9 days to 11.0 +/- 0.8 days (p < 0.01) in nontreated and NKR-P1-depleted F1 animals, respectively. Other sequelae included earlier onset of GvH manifestations, pronounced damage of primary and secondary lymphatic organs, substantial increase in spleen index, and lower CD4(+)/CD8(+ )ratios over the course of progressing GvHD. Our results underline the important immunoregulatory role of NK cells as a first defensive line acting on the alloreactivity of donor-derived immunocompetent cells in this model of solid organ transplantation.
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PMID:Correlation between graft-versus-host induced immunosuppression and host natural killer cell activity in small bowel transplantation. 879 63

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

A structure-based designed peptide has been engineered to exhibit the same molecular surface as a portion of the CDR3-like region in domain 1 of the murine CD4 molecule. Earlier in vitro experiments indicated that this analog, known as rD-mPGPtide, inhibited T-cell proliferation in mixed lymphocyte reactions and blocked activation of both normal CD4+ T cells and T-cell lines after T-cell receptor triggering. In addition, rD-mPGPtide proved to be a potent inhibitor in vivo of CD4+ T-cell-mediated experimental allergic encephalomyelitis disease in the SJL mouse model. In this current report, we have evaluated the potential of rD-mPGPtide for suppressing the development of graft-versus-host disease (GVHD) in an irradiated major histocompatibility complex (MHC)-haploidentical murine bone marrow transplantation (BMT) model [(B6 x DBA/2)F1-->(B6 x CBA)F1 (950 cGy)]. Our results indicated that early administration of rD-mPGPtide was effective in the inhibition of alloreactive responses of the donor T cells against the host and thus delayed or prevented the onset of GVHD. The median survival time of animals treated with rD-mPGPtide was enhanced as much as four-fold with as little as a single dose of peptide at the time of transplant. Decreased alloreactivity was indicated by phenotypic and functional analysis of positively selected thoracic duct lymphocytes 4 days after transplant and by histopathological examination of skin and gastrointestinal tissue samples 4 weeks later. Therefore, the administration of a CD4-CDR3 peptide is an efficacious approach against the development of GVHD during allogeneic BMT.
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PMID:Inhibitory effect of a CD4-CDR3 peptide analog on graft-versus-host disease across a major histocompatibility complex-haploidentical barrier. 887 2

Recent studies have demonstrated that the treatment of mice with anti-gp39 antibodies impairs T-cell functions in the murine collagen type II-induced arthritis model, in acute semi-allogenic graft-versus-host disease, and in the allo-specific CTL-reaction, that is, reactions that are believed to be mediated by Th1-type T cells. On the other hand, the administration of anti-gp39 antibody did not influence Th2 T-cells responses, suggesting that CD40-CD40L interactions are more crucial for Th1 than Th2 T-cell development. Recent studies also demonstrate that dendritic cells (DC) are capable of driving a Th1 T-cell response that is mediated by IL-12. In addition, stimulation of CD40 on human monocytes results in IL-12 production, suggesting that activated T cells expressing CD40L may directly induce the production of IL-12 by antigen-presenting cells, thus allowing for the generation of a Th1 T-cell response in the absence of intracellular pathogens. We investigated whether the CD40-CD40L interaction was important in the production of IL-12 by DCs in an in vitro system that allowed precise control of cytokine concentrations. Initially we showed that FACS-purified mouse spleen DCs produce high amounts of IL-12 p40 in response to CD40 crosslinking by CD40L-expressing fibroblasts. We then demonstrate that DCs also produce IL-12 p40 in a more physiologic system using purified DCs pulsed with ovalbumin (OVA) and then cultured with LECAM-1hi T cells from ovalbumin T-cell receptor transgenic mice. Finally, we show that IL-10 has a potent capacity to shut down CD40-induced IL-12 p40 secretion; and, in addition, IL-4 partially inhibits CD40-induced IL-12 p40 secretion and enhances IL-10-mediated inhibition in an additive fashion. We also investigated the in vivo relevance of this interaction in an experimental model for a Th1-mediated disease, the hapten reagent (TNBS)-induced colitis. The administration of anti-gp39 (CD40L) antibodies during the induction phase of the Th1 response completely prevented IFN-gamma production by CD4 T cells from the intestinal lamina propria and also the clinical and histological evidence of disease. In further studies we showed that the prevention of disease activity was due to an inhibition of IL-12 secretion. Thus, the injection of recombinant IL12 p75 heterodimer into TNBS + anti-gp39-treated mice reversed the effect of anti-gp39 and resulted in severe disease activity. In conclusion, these findings suggest that DCs produce IL-12 in response to CD40 signaling, that a mechanism by which IL-4 may induce Th2 development is by acting with IL-10 to inhibit IL-12 production by DCs, and that the CD40L-CD40 interaction is crucial for the IL-12-dependent priming of Th1 T cells in vivo.
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PMID:Interleukin-12 production by dendritic cells. The role of CD40-CD40L interactions in Th1 T-cell responses. 895 22

We have determined the capacity of donor CD4 and CD8 T cells to mediate liver injury in the B10.D2 (donor) into BALB/c (host) chronic graft-versus-host disease (GVHD) model. First, we compared the effects of treating GVHD mice with anti-CD4 or anti-CD8 versus no treatment on the liver histology scores and elevated serum IgE levels in this model. We also examined the abilities of purified donor total T, CD4, and CD8 cells to mediate hepatic GVHD lesions. Anti-CD4 and anti-CD8 treatments caused profound depletion of peripheral CD4+ and CD8+ cells, respectively, and produced a relative enrichment of the CD8+ and CD4+ cells in the liver. Hepatic GVHD lesions and elevated serum IgE concentrations were both suppressed by anti-CD4 treatment. Anti-CD8 treatment had no effect on the severity of hepatic lesions and caused a significant increase in serum IgE levels. Attempts to induce hepatic GVHD with purified donor CD4 and CD8 cells were inconclusive because the onset of liver lesions was delayed and the lesions in both groups were contaminated by the opposite subset. Altogether, our results indicate that both hepatic lesions and elevated serum IgE concentrations in this GVHD model are dependent on donor CD4 cells. Donor CD4 cells mediated hepatic GVHD in the absence of CD8 cells. Donor CD8 cells did not produce hepatic GVHD in the absence of CD4 cells and appeared to be dependent on CD4 cells.
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PMID:Contributions of donor CD4 and CD8 cells to liver injury during murine graft-versus-host disease. 897 Jun 18

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