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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 studied the T cell repertoire and the mechanism of tolerance in two patients with severe combined immunodeficiency transplanted with HLA mismatched fetal liver stem cells. They are 17 and 5 years old now, healthy, and show normal immunoresponses to recall antigens. Their T cells are of donor origin, whereas monocytes and B cells remained of the host. The NK cells have different sources since in one patient they derive from the donor and in the other one from the host. Despite the HLA mismatch between donor and host cells, no acute or chronic graft-versus-host disease was observed. In vitro experiments with PBMC showed specific nonresponsiveness for the HLA antigens expressed by the host cells. However, an extensive clonal analysis showed that CD4+ and CD8+ host-reactive T cell clones recognizing class II and class I HLA molecules of the host, respectively, were present in the peripheral blood of both patients. Limiting dilution experiments indicated that the frequency of CD8+ host-reactive cells was in the same range as that observed for alloreactive T cells. In contrast, no donor reactive CD8+ T cells could be isolated. Host-reactive CD4+ and CD8+ T cell clones were normal in their capacity to produce IL-2, IFN-gamma, GM-CSF and IL-5, but they failed completely to synthesize IL-4. In addition, CD4+ T cell clones from patient RV secreted very high levels of IL-10. Interestingly, exogenous IL-10 was able to inhibit the proliferative responses of the CD4+ host-reactive T cell clones. Our data demonstrate that host-reactive cells are not deleted from the donor T cell repertoire following allogenic fetal liver stem cell transplantation. Therefore, in vivo tolerance between the host and the donor is maintained by a peripheral autoregulatory mechanism in which cytokines may play a role.
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PMID:T cell repertoire and tolerance after fetal stem cell transplantation. 135 21

We suggest that acute GVHD after marrow transplantation reflects (1) host injury due to the conditioning regimen followed by the production of inflammatory cytokines; (2) stimulation of mature donor T cells in the milieu of increased cell surface expression of leukocyte adhesion molecules and HLA molecules, followed by the autocrine production of IL-2; and, finally, (3) recruitment and activation of additional mononuclear effector cells from donor marrow progenitors, which produce additional inflammatory cytokines, thus sustaining the response. The second step is critical for the amplification of the systemic inflammatory response, and it is absence in autologous, syngeneic, and T-cell-depleted transplants. These T cells may also contribute to the inflammatory cytokine network. Acute GVHD can occur in the absence of primary tissue injury in such settings as transfusion-related GVHD; however, it is likely that a greater HLA disparity between donor and host is required. We propose that inflammatory cytokine production is the final common pathway of acute GVHD. If this model is correct, control of cytokine dysregulation at any of several points should control GVHD. Further studies of GVHD and investigations of cytokine antagonists (eg, IL-4 or IL-10) or combinations of antagonists such as IL-1ra and soluble TNF receptor or pentoxifylline will allow us to determine the validity of this hypothesis.
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PMID:Cytokine dysregulation and acute graft-versus-host disease. 146 11

Cyclosporin A (CsA) is a potent inhibitor of cytokine (IL-2-IL-6, IFN gamma) production by CD4+ T lymphocytes stimulated via the T cell antigen receptor pathway. This action results in indirect inhibitory effects on the growth and differentiation of B lymphocytes (IL-4 and IL-6). Using experimental models, it has also been shown that the functional activities of mononuclear phagocytes (IFN-gamma) and other antigen-presenting cells, production of mast cells (IL-3) and eosinophils (IL-5) and the activity of natural killer (NK) cells may be inhibited indirectly by CsA. In addition, however, CsA blocks B cell responses to Ca(2+)-dependent signals (e.g., anti-IgM) downstream of phosphatidyl inositol diphosphate hydrolysis; Ca(2+)-independent responses (e.g., to LPS or IL-4) are largely unaffected. In general terms, the functions of macrophages are unchanged or reduced in the presence of CsA. These include phagocytic activity in vitro and in vivo, chemotactic migration, superoxide and H2O2 production, protein (including monokine) secretion and MHC gene product expression. Antigen presentation (e.g., by epidermal Langerhans cells) may be affected, especially at high drug concentrations. There is recent evidence that CsA inhibits mediator (histamine and prostaglandin) release from human mast cells and that mucosal mast cell numbers may be diminished in CsA-treated animals exhibiting graft-versus-host disease or helminth infections.
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PMID:The effects of cyclosporin A on non-T cell components of the immune system. 150 9

These studies examined the role of cytokines in chronic autoimmune graft-versus-host disease (GVHD) in B6D2F1 mice injected with lymphoid cells from DBA/2 mice. Anti-interleukin (IL)-4 and anti-interferon (IFN)-gamma mAb, or IFN-gamma, were used in vivo to modulate B cell hyperactivity and disease. Kinetic experiments showed that, 2-3 weeks after induction, GVH mice had 100x elevated serum IgE, while IgG1 and IgG2a were 10x above normal. Early treatment with anti-IL-4 mAb or IFN-gamma decreased serum IgE and IgG1 and had no effect on IgG2a. Anti-IFN-gamma mAb treatment increased serum IgE and IgG1 while reducing IgG2a. This increase in serum immunoglobulins could be correlated with an increased spontaneous secretion of IL-4, IL-5, and IL-6 in spleen cell cultures from anti-IFN-gamma mAb-treated GVH mice. While neither anti-IFN-gamma nor IFN-gamma treatments altered the disease course, anti-IL-4 treatment delayed proteinuria and death in GVH mice. These observations suggest an important role for IL-4 in immune complex-mediated glomerulonephritis in chronic GVHD.
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PMID:Effects of in vivo administration of interferon (IFN)-gamma, anti-IFN-gamma, or anti-interleukin-4 monoclonal antibodies in chronic autoimmune graft-versus-host disease. 159 85

Four to six weeks after total lymphoid irradiation (TLI), there is a selective deficit in the CD4+ T cells which secrete IL-2, proliferate in the MLR, and induce GVHD (Th1-like functions). A similar deficit in CD4+ T cells which secrete IL-4 and help antibody responses (Th2-like functions) is not observed. In the present study, shielding of the thymus with lead during TLI increased the Th1-like functions of CD4+ cells. Mice without thymus shields showed a marked selective reduction in the medullary stromal cells identified with the monoclonal antibody, MD1, and the severe reduction was prevented with thymus shields. Thus, shielding the thymus prevents the depletion of thymic medullary stromal cells and allows for a rapid recovery of Th1-like functions in the mouse spleen after TLI. Th2-like functions recover rapidly after TLI whether or not the thymus is irradiated.
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PMID:Thymic irradiation inhibits the rapid recovery of TH1 but not TH2-like functions of CD4+ T cells after total lymphoid irradiation. 168 27

We studied a severe combined immunodeficiency (SCID) patient who received transplantations with completely HLA-mismatched fetal liver and thymus from two different donors. The patient is now 14 years old, healthy and shows normal immunoresponses to recall antigens. His T cells are of donor origin, whereas the monocytes, B cells, and natural killer (NK) cells are of the recipient. The successful immunological reconstitution raised questions as to how T and B cells could collaborate across an HLA barrier and how tolerance was achieved. We have shown that tetanus toxin-specific T cell clones isolated from this patient recognized this antigen in the context of host and not of donor HLA-DR, indicating that those cells were educated in the host environment, presumably the thymus. Despite this, an unexpectedly high frequency of host-reactive clones was found that could recognize MHC antigens of the host. It was particularly striking that CD8+ CTL clones were obtained that recognized class I MHC antigens on the host cells. Nevertheless, the patient did not show any sign of acute or chronic graft-versus-host disease (GVHD). These data indicated that no or only incomplete clonal deletion had taken place in this patient and suggest the presence of a peripheral suppressor mechanism. Thus far, we have no indication for the existence of suppressor T cells. Inasmuch as it was found that host-reactive T cells fail to produce IL-4, which is exceptional for CD4+ T cells, we are exploring the possibility that abnormal cytokine production patterns of host-reactive T cells are associated with suppression of these cells in vivo.
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PMID:A SCID patient reconstituted with HLA-incompatible fetal stem cells as a model for studying transplantation tolerance. 168 May 8

Immunoglobulin production, particularly IgE, is known to be dysregulated in graft-vs-host disease (GVHD). We examined serum levels of the highly T-dependent Ig isotypes, IgE, IgG1, and IgG2a, in two different mouse models of GVHD. GVHD across minor histocompatibility barriers is produced by injection of B10.D2 spleen cells into 600 rad irradiated BALB/c hosts. Both strains are H2d and mls b, but differ at the minor histocompatibility antigens. As GVHD progresses there is a rapid rise in serum IgE (300-fold) and IgG1 (2.5-fold) with a peak at Day 14. Concomitantly, IgG2a falls. Serum immunoglobulin levels return to normal by 11 weeks. The rise in IgE is abolished by increased (900 rad) recipient irradiation, suggesting that host-derived factors are important. GVHD across major histocompatibility barriers is produced by injection of DBA/2 spleen cells into unirradiated or 600 rad irradiated (B6 x DBA/2)F1 hosts. Only in the irradiated recipients is there severe Ig dysregulation. In this situation there is a 100-fold rise in IgE, and 5- to 10-fold rises in IgG1 and IgG2a. While the results in GVHD across minor barriers suggest stimulation of T helper cells secreting IL-4, the increase in IgE, IgG1, and IgG2a levels in GVHD across major barriers suggests activation of IL-4 and IFN-gamma-secreting T cells. These results indicate that different mechanisms may be operating in these two models of GVH. Murine GVHD can serve as a model for studying dysgammaglobulinemias in general and for hyper-IgE formation in particular.
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PMID:Immunoglobulin dysregulation in murine graft-vs-host disease: a hyper-IgE syndrome. 235 59

Acute and chronic graft-versus-host disease (GVHD) in the parent-into-F1 model are mediated by predominantly cellular or humoral immune responses, respectively, and are strikingly different entities by 2 wk of disease. Both forms of GVHD, however, evolve from a common starting point, i.e., donor CD4+ T cell recognition of host alloantigen and IL-2 production. Our study examines the first 2 wk of GVHD to delineate the events that critically influence GVHD development. Surprisingly, both forms of GVHD are initially characterized by increased Th2 cytokine (IL-4 and IL-10) production and B cell activation which persists into wk 2. The earliest distinguishing features of acute GVHD were detectable at days 5 through 7 of disease and consisted of 1) expansion of donor CD8+ T cells, and 2) increased IFN-gamma production by donor CD4+ and CD8+ T cells. Interestingly, IFN-gamma production by donor CD4+ T cells was not seen if donor CD8+ T cells were not engrafted in comparable numbers. Chronic GVHD in the DBA-into-BDF1 model was found to be caused by a relative defect in the ability of DBA CD8+ T cells to induce acute GVHD and to produce IFN-gamma. These studies demonstrate that both acute and chronic GVHD begin as a Th2 cytokine-mediated, B cell stimulatory response. The transition to acute GVHD is critically dependent on the engraftment of donor CD8+ T cells, which terminate B cell hyperactivity by 1) eliminating activated B cells and 2) promoting IFN-gamma secretion by donor CD4+ T cells.
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PMID:Kinetics of Th1 and Th2 cytokine production during the early course of acute and chronic murine graft-versus-host disease. Regulatory role of donor CD8+ T cells. 765 Mar 73

Although acute graft-versus-host disease (GVHD) is a common complication after allogeneic bone marrow transplantation (BMT), the specific pathophysiology of tissue damage has not been elucidated. We have previously described an infiltrate of CD2+, CD8+, alpha/beta receptor+ T lymphocytes, and the upregulation of ICAM-1 in tissues with acute GVHD. We hypothesized that these infiltrating lymphocytes may secrete cytokines that could contribute to tissue damage. In the current study, we used reverse transcription (RT) polymerase chain reaction (PCR) to explore the mRNA expression of candidate inflammatory cytokines IL-1 alpha, IL-2, IL-4, IL-6, TNF-alpha, and interferon-gamma (IFN-gamma) in peripheral blood mononuclear cells (PBMC) and skin biopsies of allogeneic BMT patients with GVHD and controls. In post-BMT control PBMC (n = 10); IL-2 RNA was infrequent (20% of samples) but was significantly more frequently detectable (71%; P < 0.05) after development of acute GVHD (n = 7). IL-4 expression was also more common in PBMC from patients with acute GVHD (57% vs. 30%; P < 0.05). Consistent with the PBMC data, IL-2 and IL-4 RNA were also more frequently detectable in skin biopsies with GVHD (n = 10): 70% of samples expressed IL-2 vs. 25% of normal controls (n = 8; P < 0.05); 60% had detectable IL-4 RNA vs. 0% of controls (P < 0.05). IFN-gamma detectability (40% vs. 12%; P < 0.05) was also more frequent in GVH skin. For both PBMC and skin, IL-1 alpha expression was infrequent in GVHD and controls, whereas TNF-alpha and IL-6 were expressed in nearly all samples. These data suggest that upregulated expression of IL-2, IL-4, and IFN-gamma may be part of the inflammatory cascade of human acute GVHD, while IL-1 alpha, TNF-alpha, and IL-6 are not discriminatory for the inflammation observed at the time of initial GVHD diagnosis.
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PMID:The tissue expression of cytokines in human acute cutaneous graft-versus-host disease. 765 63

In a fully MHC plus multiple minor antigen-mismatched murine bone marrow transplantation (BMT) model, we have demonstrated that a short course of high dose IL-2, begun on the day of BMT, protects against graft-versus-host disease (GVHD). This inhibitory effect is directed against donor CD4+ cells. To determine whether the mechanism of IL-2-induced GVHD protection involves clonal deletion or anergy of host-reactive donor T helper cells (Th), we performed limiting dilution analyses to measure the frequency of activated Th that reacted to donor, host, and third-party antigens in GVHD control and IL-2-protected mice. Marked and specific expansion of host-reactive Th was observed to a similar extent in GVHD control and IL-2-protected mice by day 5 after BMT, and the number of these cells in the spleen increased by several orders of magnitude between days 3 and 5 after BMT, which suggests that recirculation from other tissues occurred in this period. A high proportion (approximately 80%) of donor T cells expressed CD25 in both GVHD control and IL-2-protected mice on day 4 after BMT, which suggests a high level of bystander T cell activation. Since marked quantitative differences in the GVH response were not observed between GVHD control and IL-2-protected mice, we assessed both groups for qualitative differences in the Th response. Spleen cells isolated in the first 8 days after BMT were cultured with host-type, donor-type, or third-party stimulators or without stimulators, and cytokines were measured in supernatants harvested at 24 hr. GVHD was associated with marked increases in supernatant IFN-gamma levels from day 3 to day 6 after BMT, and with increases in IL-2 levels compared with naive A/J controls or syngeneic BMT controls stimulated with host antigens. Production of these cytokines was specifically induced by host-type antigens. Supernatants from spleens of IL-2-treated mice showed delayed kinetics of IFN-gamma production, and tended to contain higher levels of IL-4 in response to host antigen compared with GVHD controls on days 2 and 4 after BMT. Both IL-4 and IFN-gamma were produced almost exclusively by CD4+ cells in spleens of GVHD control and IL-2-protected mice on day 4. However, no consistent difference was observed between the groups in supernatant IL-2 or IL-10 levels, ruling out a simple Th1 to Th2 switch.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Inhibition of graft-versus-host disease by interleukin-2 treatment is associated with altered cytokine production by expanded graft-versus-host-reactive CD4+ helper cells. 767 98


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