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)

A 'cytokine storm' consisting of IL-1, IL-2, IL-12, IFNgamma and TNFalpha is considered important in the development of graft-versus-host disease (GvHD). These cytokines activate effector cells or damage host tissues. Cord blood transplantation has been associated with a low incidence of GvHD. We hypothesized that the low incidence of GvHD relates to the cord mononuclear cells being poor producers of pro-inflammatory cytokines. The cytokine profile (IL-1alpha/beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IFNgamma and TNFalpha) of cord blood cells induced by immune stimuli was determined in heparinized whole blood. Compared to adult, cord blood CD3+ and NK cells produced less IFNgamma, less cord blood CD3+ cells and monocytes produced TNFalpha and less monocytes produced IL-1alpha/beta. Although more cord T cells produced IL-2 compared to adult T cells at 4 h, adult T cells produced more at 24 h. Cord blood had similar proportions of monocytes to adult producing IL-6, IL-10 and IL-12. Both adult and cord mononuclear cells constitutively expressed receptors for IFNgamma and TNFalpha but not IL-12. In contrast to the adult cells, cord CD3+ and NK cells did not express IL-12 receptor but did up-regulate IL-10 receptor after mitogenic stimulation. The findings of this study indicate that the cord blood cytokine-receptor network is biased towards anti-inflammatory activity compared to adult and helps to explain the decreased incidence of GVHD in cord blood transplantation.
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PMID:Intracellular cytokine production and cytokine receptor interaction of cord mononuclear cells: relevance to cord blood transplantation. 1058 39

IL-10 is a potent immunosuppressant which inhibits allo-antigen-specific T cell responses. In addition, IL-10 is a strong endogenous anti-inflammatory cytokine. To investigate the role of IL-10 in the induction of acute GVHD following allogeneic bone marrow transplantation (BMT) we performed a prospective study on spontaneous IL-10 production by peripheral blood mononuclear cells (PBMNC) in 84 patients admitted for allogeneic BMT. High spontaneous IL-10 production by PBMNC at the time of admission and prior to any preparative treatment correlated with a subsequent low incidence of GVHD and transplant-related mortality (8%), as compared to patients with low or intermediate IL-10 production (50%, P < 0. 01). Our data demonstrate the prognostic significance of increased IL-10 production in BMT patients and suggest a major role of IL-10 in maintaining immunobalance in the setting of allogeneic BMT. Bone Marrow Transplantation (2000) 25, 237-241.
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PMID:Prognostic significance of increased IL-10 production in patients prior to allogeneic bone marrow transplantation. 1067 93

Administration of the immunosuppressive drug cyclosporine after syngeneic or autologous bone marrow transplantation elicits a T-lymphocyte-dependent autoimmune syndrome similar to graft-versus-host disease (GVHD). The onset of this autoaggression syndrome, termed syngeneic GVHD, is associated with the development of a highly restricted repertoire of CD8+ autoreactive T cells that recognize a peptide from the invariant chain, termed CLIP, presented by major histocompatibility complex (MHC) class II molecules. Clonal analysis reveals 2 distinct subsets of autoreactive T cells defined by their activation requirement for either the N-terminal or the C-terminal flanking regions of CLIP and by their cytokine profile. The studies here reveal that the autoreactive T-cell clones requiring the N-terminal flanking region of CLIP produce type 1 cytokines (interferon [IFN]-gamma, interleukin [IL]-2, and tumor necrosis factor-alpha). In contrast, the autoreactive T-cell clones that require the C-terminal flanking region of CLIP produce type 2 cytokines (IL-4, IL-10, transforming growth factor-beta). As assessed in a local graft-versus-host reaction assay, the N-terminal flanking-restricted clones mediate changes consistent with acute GVHD, whereas the clones responsive to the C-terminal flanking region do not. Moreover, the autoreactive T-cell clones restricted by the C-terminal flanking region of CLIP ameliorate the pathogenic potential of the cells responsive to the N-terminal flanking region of CLIP. The mechanism accounting for this regulatory affect appears to be the downregulation of mRNA message for type 1 cytokines (IFN-gamma and IL-2). The C-terminal-restricted autoreactive T-cell clones, however, could manifest disease with dermal changes similar to those seen in chronic syngeneic GVHD, provided that IFN-gamma was present. Consistent with these observations was the demonstration that type 1 cytokines are preferentially detected during the acute phase of syngeneic GVHD, whereas type 2 cytokines dominate during the chronic phase. The results suggest that acute and chronic syngeneic GVHD is mediated by distinct autoreactive T cells, which are separated by their fine specificity for the CLIP-MHC class II complex and by their cytokine profiles.
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PMID:Complexity of effector mechanisms in cyclosporine-induced syngeneic graft-versus-host disease. 1070 95

Peripheral blood stem cells (PBSC) obtained from granulocyte-colony stimulating factor (G-CSF)-mobilized donors are increasingly used for allogeneic transplantation. Despite a 10-fold higher dose of transplanted T cells, acute graft-versus-host disease (GVHD) does not develop in higher proportion in recipients of PBSC than in recipients of marrow. T cells from G-CSF-treated experimental animals preferentially produce IL-4 and IL-10, cytokines characteristic of Th2 responses, which are associated with diminished GVHD-inducing ability. We hypothesized that G-CSF-mobilized PBSC contain antigen-presenting cells, which prime T-lymphocytes to produce Th2 cytokines. Two distinct lineages of dendritic cells (DC) have been described in humans, DC1 and DC2, according to their ability to induce naive T-cell differentiation to Th1 and Th2 effector cells, respectively. We have used multicolor microfluorometry to enumerate DC1 and DC2 in the peripheral blood of normal donors. G-CSF treatment with 10 to 16 microg/kg per day for 5 days increased peripheral blood DC2 counts from a median of 4.9 x 10(6)/L to 24.8 x 10(6)/L (P =.0009), whereas DC1 counts did not change. Purified DC1, from either untreated or G-CSF treated donors, induced the proliferation of allogeneic naive T cells, but fresh DC2 were poor stimulators. Tumor necrosis factor-alpha (TNF-alpha)-activated DC1 induced allogeneic naive T cells to produce IFN-gamma, which is typical of Th1 responses, whereas TNF-alpha-activated DC2 induced allogeneic naive T cells to produce IL-4 and IL-10, which are typical of Th2 responses. PBSC transplants contained higher doses of DC2 than marrow transplants (median, 2.4 x 10(6)/kg versus 0.5 x 10(6)/kg) (P =.006), whereas the dose of DC1 was comparable. Thus, it is conceivable that transplantation of G-CSF-stimulated PBSC does not result in overwhelming acute GVHD because the graft contains predominantly Th2-inducing DC. Adoptive transfer of purified DC2 may be exploited to induce immune deviation after transplantation of hematopoietic stem cells or organ allografts. (Blood. 2000;95:2484-2490)
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PMID:Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells. 1119 28

Allogeneic stem cell transplantation (SCT) represents a curative treatment option for patients with leukemia and lymphoma. T lymphocytes contained in the allograft mediate a graft-versus-leukemia (GVL) effect and prevent graft rejection; however, T cells also initiate graft-versus-host disease (GVHD). Identification of T cell populations which mediate a GVL effect and prevent rejection with reduced GVHD will likely improve transplantation outcome. T cells exist in four functionally-defined populations, the CD4+, Th1/Th2 and CD8+, Tc1/Tc2 subsets. Th1-type CD4 cells primarily secrete type I cytokines (IL-2 and IFN-gamma), whereas Th2 cells secrete type II cytokines (IL-4, IL-5, and IL-10). Similarly, the CD8+ Tc1 and Tc2 cells differentially secrete the type I and type II cytokines, respectively. In addition to cytokine secretion, Tc1 and Tc2 populations mediate cytolytic effects, with Tc1 cells utilizing both perforin- and fas-based killing pathways, whereas Tc2 cells primarily utilize perforin-mediated cytolysis. In murine transplantation models of graft rejection, GVHD, and GVL effects, we have evaluated such functional T cell subsets for their ability to differentially mediate and regulate transplantation responses. These studies demonstrate that donor Th2 cells do not initiate acute GVHD, and can regulate the GVHD mediated by unmanipulated donor T cells without impairing alloengraftment. Additional experiments have shown that allospecific donor Tc2 cells result in reduced GVHD, and mediate a significant GVL effect. Thirdly, we have demonstrated that non-host reactive Tc2 cells with veto-like activity can potently abrogate marrow rejection independent of GVHD. Together, these results demonstrate that functionally-defined donor Th2 and Tc2 populations play an important role in the regulation of GVHD, the prevention of graft rejection, and the mediation of GVL effects, and suggest that utilization of Th2 and Tc2 cells in clinical allogeneic SCT may have potential for improving treatment outcome.
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PMID:Th2 and Tc2 cells in the regulation of GVHD, GVL, and graft rejection: considerations for the allogeneic transplantation therapy of leukemia and lymphoma. 1083 Jul 30

A deficiency of neonatal T lymphocytes to express CD154 antigen in response to ionomycin and phorbol 12-myrsistate 13-acetate (PMA) stimulation or after CD3 cross-linking has been described. In the present report we describe that CD45RA+ newborn cells are able to synthesize and express CD154 at similar or even higher levels than adult cells in response to ionomycin and cAMP-elevating agents which trigger the protein kinase A (PKA) -mediated metabolic pathway. Peak CD154 protein concentrations in newborn cells were found between 4 and 8 hr after stimulation with ionomycin and dibutyryl cAMP. These agents, however, did not induce expression of the early activation antigen CD69. Surface levels of CD154 did not correlate with specific mRNA concentration, indicating that dibutyryl cAMP up-regulates CD154 by acting at a post-transcriptional stage. The CD154 antigen induced by PKA activation of newborn cells was functional, since upon binding to CD40 on B lymphocytes in the presence of interleukin-4 (IL-4), it promoted immunoglobulin heavy-class switching to IgE. We also found a different pattern of cytokine production between neonatal and adult CD4+ T cells. In response to ionomycin and dibutyryl cAMP, cord blood cells were more prone than adult lymphocytes to secrete the T helper type 2-derived immunosuppressive cytokines IL-4 and IL-10. Taking into account that the feto-maternal environment is rich in cAMP-elevating agents, the reduced risk of graft versus host disease associated with cord blood trasplantation, as compared with the risk with adult bone marrow cell transplants, may be due to the bias of neonatal cells to differentiate towards the T helper type 2 functional cell subset.
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PMID:Induction of functional CD154 (CD40 ligand) in neonatal T cells by cAMP-elevating agents. 1092 69

Cytokine levels in sera from 14 patients undergoing allogeneic bone marrow transplantation (alloBMT) or donor lymphocyte infusion (DLI) were sequentially measured to evaluate the roles of cytokines in clinical graft-versus-host disease (GVHD). In clinical courses, interleukin (IL)-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were measured by enzyme-linked immunosorbent assay. Among the evaluable cases, 6 patients developed acute GVHD. Serum IL-5 levels increased to more than 100 pg/mL in 5 of the 6 patients before, or simultaneously with, the clinical manifestation of acute GVHD. Elevation of IL-5 was transient in 3 patients. In the other 2 patients who showed regimen-related toxicity and/or thrombotic microangiopathy as well as acute GVHD, remarkable and sustained elevation of the serum IL-5 level was observed. In 7 patients without acute GVHD, IL-5 levels remained below 100 pg/mL. An association of acute GVHD was less prominent with TNF-alpha than with IL-5 in our study. Elevation of IL-6 was associated with infections. In 2 patients with severe extensive chronic GVHD, serum IL-10 was elevated in parallel with exacerbation of clinical symptoms. Our findings suggest that an elevated serum IL-5 level may be a marker of acute GVHD.
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PMID:Kinetics of serum cytokines after allogeneic bone marrow transplantation: interleukin-5 as a potential marker of acute graft-versus-host disease. 1097 16

Scleroderma (SSc) is a fibrosing connective tissue disease that is poorly responsive to any treatment, including immune suppression. SSc shares many characteristics with chronic graft-versus-host disease (GVHD). Because the immunomodulatory drug thalidomide has proven beneficial in chronic GVHD, we studied the immune response and clinical effects of thalidomide in SSc patients. We treated 11 SSc patients with thalidomide in an open label, dose escalating, 12 week study. Histologic comparison of skin biopsies showed changes in skin fibrosis and an increase in epidermal and dermal infiltrating CD8(+) T cells with thalidomide treatment. In thalidomide-treated SSc patients, plasma levels of IL-12 and TNF-alpha increased, while plasma IL-5 and IL-10 levels remained unchanged. These changes were associated with clinical effects, including dry skin, dermal edema, transient rashes, decreased gastroesophageal reflux symptoms, and healing of digital ulcers. When SSc PBMCs activated by anti-CD3 mAb were exposed to thalidomide, increases in both production of IL-2, IL-3, GM-CSF, and IFN-gamma and T cell expression of CD40L were observed. Thalidomide therefore appears to induce immune stimulation in SSc patients in association with clinical changes. However, it remains to be shown whether long-term enhancement of immune responses in SSc patients is clinically beneficial.
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PMID:Immune stimulation in scleroderma patients treated with thalidomide. 1102 51

We have shown previously that increased levels of hsp70, and antibodies reactive with hsp70 parallel the onset and severity of graft-versus-host disease (GVHD) in a parent --> (DA x LEW)F1 rat model. In this study we have assessed the effect of reducing the levels of the 70 kDa heat shock protein (hsp70), on the morbidity and mortality of acute GVHD in (DA x LEW)F1 rats. The reduction was accomplished by the administration of 15-deoxyspergualin (DSG), an immunosuppressive agent which binds to a constitutively expressed member of the 70 kDa heat shock protein family. DSG administered via three different protocols reduced GVHD-associated morbidity. One of the regimens, which consisted of intermittent DSG administration, also significantly reduced GVHD associated mortality. This DSG treatment reduced hsp70 levels in spleen and lymph nodes, inhibited anti-hsp70 antibody production, and diminished the serum levels of IL-2, IFN-gamma, TNF-alpha, and IL-10. IL-4 levels in the serum did not change during GVHD and were not effected by DSG. These results show that the mechanism of DSG immunosuppressive effect in rat GVHD may involve DSG's capacity to bind to hsp70, which in turn may lead to a decrease in levels of circulating anti-hsp70 antibodies, and reduced production of cytokines.
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PMID:Reduced levels of Hsp70 result in a therapeutic effect of 15-deoxyspergualin on acute graft-versus-host disease in (DA x LEW)F1 rats. 1104 61

We show that there are differences in the soluble factors in cord blood (CB) and adult serum and that these differences play a role in T cell function. Thus, the mitogen and alloantigen-specific proliferative response of adult T cells was enhanced with increasing concentrations of adult serum and CB serum, but to a lesser extent with CB serum. In addition, proliferation of T cells induced by stimulation through the T cell receptor alone (via CD3 stimulation), could be enhanced with adult but not CB serum. However, CB serum enhanced the IL-2-specific proliferative response of pure T cells whereas adult serum did not. To determine whether there was an anti-inflammatory cytokine within CB serum which could induce these results, we assayed our serum samples for anti-inflammatory cytokines. IL-13 could not be detected in any serum sample, whereas IL-10 could be detected in adult but not CB serum (P < 0.002). However, there was a significant difference in the levels of macrophage colony stimulating factor (M-CSF) detected in adult and CB serum samples (P < 0.01). M-CSF was detected in 6/7 CB serum samples (mean +/- SD was 3.8 +/- 2.3 ng/ml) and 0/5 adult serum samples. Furthermore, anti-M-CSF antibody restored the reduced allo-response of T cells incubated in CB serum. Thus, M-CSF may act as a suppressor factor in CB serum. Whether this is sufficient to explain the lack of an allo-response by the foetus to the mother, or the reduced graft-versus-host disease when CB is used instead of bone marrow in stem cell transplantation, is yet to be determined.
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PMID:Macrophage colony stimulating factor (M-CSF) within cord blood sera may be partially responsible for the reduced proliferation of cord blood T cells. 1112 4


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