Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Following a course of cyclosporine, syngeneic rat radiation chimeras consistently develop a GVHD-like syndrome. Correlation of the thymic immunopathology with conditions leading to syngeneic graft-versus-host disease (sGVHD) suggested the hypothesis that reconstitution of the normal thymic microenvironment after CsA is necessary for self-tolerance. When thymic regeneration is impaired, as in rats receiving previous mediastinal irradiation, then self-reactive effector cells are not regulated and proceed to damage the target tissues. Alternately, it could be argued that the observed thymic abnormalities are irrelevant to sGVHD. To test the primary hypothesis, post-CsA thymic reconstitution was prevented by total thymectomy in unirradiated rats. These rats consistently developed acute type sGVHD seen at 7 and 21 days post-CsA while rats from the CsA-treated sham thymectomy control group failed to develop sGVHD. Because thymectomy prior to CsA blocks sGVHD, most likely the peripheral effector cells in the post-CsA thymectomy group were derived from the CsA-altered thymus. The absence of sGVHD in the sham group indicates that the thymus led to active regulation of these cells after stopping CsA. If regeneration of the thymus restored only negative selection, then the sham thymectomy group should have also developed sGVHD. Flow cytometry and morphology of the spleen and lymph nodes demonstrated that the thymectomized rats, like CsA-treated radiation chimeras, experienced a significant delay in maturation of T cells following CsA. In contrast to the usual model in radiation chimeras, however, the post-CsA thymectomized rats did not convert to chronic type sGVHD. The importance of an abnormal thymus for this transition was confirmed in syngeneic radiation chimeras. Thymectomy after CsA in these rats also blocked the rapid transition to chronic sGVHD.
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PMID:Prevention of syngeneic graft-versus-host disease by recovery of thymic microenvironment after cyclosporine. 192 47

Previous studies have demonstrated that short-term administration of cyclosporine leads to immunopathologic changes in the thymus, including medullary involution, loss of Hassall's corpuscles, and decreased class II antigen expression. Generally these changes are rapidly reversible. In rats treated with mediastinal irradiation, however, these changes are irreversible and usually associated with autologous or syngeneic graft-vs.-host disease (pseudo-GVHD). This study describes the immunopathology of the thymus after long-term administration of CsA (7 mg/kg/day, up to 140 days) and monitors the recovery post-CsA. The medulla was markedly involuted at the end of CsA, regardless of duration. The relative size of the medulla showed good recovery. Long-term CsA, however, profoundly delayed or prevented the recovery of Hassall's corpuscles and normal expression of class II antigen. The epithelial cells in Hassall's corpuscles totally disappeared at the end of CsA administration. Following 7 or 28 days of CsA, the Hassall's corpuscles recovered within one month. After 70 days CsA, recovery was delayed until the second month, while after 140 days, Hassall's corpuscles were not present even 2 months post-CsA. Class II antigen was decreased in the subcapsular and juxtamedullary regions at 140 days as well as 1 and 2 months post-CsA. Paralleling the thymic immunopathology, acute and chronic pseudo-GVHD were observed in the skin, tongue, liver, intestines, lacrimal glands, bronchi, and intestines following long-term CsA.
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PMID:The thymus and prolonged administration of cyclosporine. Irreversible immunopathologic changes associated with autologous pseudo-graft-versus-host disease. 211 78

Recognized manifestations of acute graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract include secretory diarrhea, abdominal pain, and, at times, hemorrhage. In a review of 469 patients undergoing allogeneic bone marrow transplantation (BMT) from matched sibling donors at our institution, we have recognized a syndrome of upper GI GVHD. This syndrome, presenting clinically as anorexia, dyspepsia, food intolerance, nausea, and vomiting, was recognized and confirmed histologically in 62 patients (13% by Kaplan-Meier projection) at the initiation of systemic GVHD therapy, a subset of the 197 patients developing grade II through IV GVHD. These 62 patients with upper GI GVHD were significantly older than the overall BMT population and older than the cohort with grade II through IV GVHD, as well. Of the 62 patients, 25 had upper GI GVHD accompanied only by limited (stage 1 and 2) skin GVHD; 13 others with upper GI GVHD plus limited skin involvement at initial presentation later progressed to more extensive multiorgan involvement; 24 others presented with upper GI along with other organ GVHD. This upper GI GVHD syndrome, first recognized at our center in 1983, has been diagnosed with increasing frequency (22% +/- 5%) in the most recent 5-year interval. The upper GI GVHD syndrome is more responsive to immunosuppressive therapy than grade II GVHD defined by Seattle criteria, with complete and continuing responses to treatment observed in 71% +/- 17% (95% confidence interval) of those with the upper GI GVHD syndrome compared with only 37% +/- 10% complete responses in other patients with grade II GVHD (P = .002). Patients failing immunosuppressive therapy for upper GI GVHD often progress to symptomatic lower GI involvement, suggesting that this syndrome may be an earlier and perhaps more treatable manifestation of this unique intestinal immunopathology, which is followed by chronic GVHD in 74% of patients. While upper GI GVHD symptoms are nonspecific and require invasive histologic and microbiologic studies to confirm the diagnosis, we believe this syndrome has been underreported after allogeneic BMT and propose its recognition within the clinical GVHD scoring system.
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PMID:Acute upper gastrointestinal graft-versus-host disease: clinical significance and response to immunosuppressive therapy. 237 89

Cyclosporine-induced pseudo-graft-versus-host disease (CIPGVHD) in syngeneic or autologous rat marrow chimeras has clinical and histologic features closely resembling classic graft-versus-host disease in the allogeneic chimera. We describe here the pathology and immunopathology of the usual target tissues in CIPGVHD developing in the first week following CsA (early group). The findings are constrasted to the CIPGVHD developing during the second week post-CsA (later group). Six of 9 rats in the early group had acute-type CIPGVHD in the tongue, skin, liver, intestines, and mainstem bronchi. In general, the lymphocytic infiltrates in these tissues were in intimate contact with injured epithelial cells. The intestines had multiple apoptotic lesions. Class II antigen was prominent in the tongue mucosa, but only patchy expression was evident in 2 skin biopsies. All of the lymphocytes infiltrating the mucosa were CD8+(OX-8)/CD4-(W3/25) T cells (OX-19+). Most of the lymphocytes in the lamina propria expressed CD4 as well as CD8 markers, suggesting coexpression. In the later group, 6 of 7 rats had chronic-type CIPGVHD (1 with acute and chronic) while 1 rat had no GVHD (P = .02, Fisher's exact test compared with the early group). These animals had features characteristic of established chronic GVHD in the skin, tongue, liver, intestines, and salivary glands. Fibrosis of the dermis and lamina propria was prominent in the skin and tongue. Submucosal fibrosis was increased in the small intestine. The salivary glands had an interstitial infiltrate and fibrosis with loss of ducts and glands. Class II antigen was prominent in the epidermis of the tongue and skin of all rats. The number of lymphocytes infiltrating the mucosa of the tongue was considerably smaller than seen in the early group. More than 90% of these cells were T cells, as detected by OX-19, and expressed both CD4 and CD8 markers. While most lamina propria lymphocytes expressed the CD4 antigen, there were significantly fewer CD8+ cells, consistent with increased numbers of CD8-/CD4+ helper-phenotype cells. The observations indicate that immediately post-CsA, the CIPGVHD is primarily acute, with epithelial infiltrates of CD8+/CD4- T cells and lamina propria infiltrates that include double-labeled cells consistent with immature thymocytes. There is a rapid transition to established chronic-type CIPGVHD by the second week. The residual mucosal infiltrate is now dominated by double-labeled T cells or thymocytes while the lamina propria infiltrate has more mature helper-phenotype T cells. Induced RT1.B/D antigen could be important in the pathogenesis of the peripheral tissue manifestations.
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PMID:Cyclosporine-induced pseudo-graft-versus-host disease in the early post-cyclosporine period. 304 92

A comparative study of the healthy skin of patients who had undergone bone marrow grafting and not developed graft-versus-host disease (GVHD) and of patients with cutaneous lesions of acute GVHD has been carried out. The aim of this study was to assess the diagnostic value of cutaneous immunopathology in the diagnosis of acute GVHD. A double-labelling immunofluorescence technique was used with a panel of monoclonal antibodies. The results showed a lack of specificity for GVHD in the distribution of Langerhans cells, but confirmed the diagnostic value of HLA-DR staining of epidermal keratinocytes. Cellular polymorphism of the T cell infiltrate in the dermis was observed (T helpers 40% and T suppressors 20%). The expression of the 55-57 Kd keratin polypeptide and of bullous pemphigoid antigen showed modification during acute GVHD while that of pemphigus antigen remained unchanged.
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PMID:Cutaneous immunological studies in diagnosis of acute graft-versus-host disease. 351 Jun 54

In a retrospective analysis lung biopsy specimens obtained postmortem from 30 consecutive allogeneic bone marrow transplant recipients who had died of either either interstitial pneumonitis (IP; 18/30 patients) or various other causes (12/30 patients) were studied for the local presence of human cytomegalovirus (HCMV) by culture, in situ hybridization, polymerase chain reaction (PCR) and immunohistochemistry for HCMV proteins. All patients suffering from IP were found to be HCMV positive in the lung biopsy. PCR revealed the highest sensitivity for HCMV detection in lung biopsies, but in 15/18 PCR-positive samples local HCMV infection could be confirmed by at least one additional technique. All the lung biopsies obtained from the 12 patients without IP were negative for HCMV by all techniques applied, except one with a weak HCMV-DNA signal in the PCR assay. The severity of the clinical, as well as histological and immunohistological alterations in the lung did not correlate with the amount of HCMV-DNA or the number of HCMV-positive cells detected in the biopsy. An increase of HLA-class II antigen and of ICAM-1 expression on the alveolar epithelium, as well as presence of activated CD8+ or CD4+ lymphocytes infiltrating only HCMV-positive lung biopsies revealed T cell-mediated immune reactions to be involved in the pathogenesis of IP. Since all analyzed patients presented with severe acute or extensive chronic graft-versus-host disease (GvHD), but only those with pulmonary HCMV infection developed IP, dissemination of HCMV appears to be the primary requirement for the initiation of IP. GvHD, however, may interfere with normal control of subsequent antiviral immune response and, thus, provoke the immunopathology of IP.
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PMID:Correlation of interstitial pneumonia with human cytomegalovirus-induced lung infection and graft-versus-host disease after bone marrow transplantation. 857 11

Cytomegalovirus (CMV) is a major pathogen in transplant recipients and AIDS patients, and the virus may also play a role in allograft rejection. Previous work from this laboratory demonstrated increased cell surface expression of the adhesion molecules ICAM-1 (CD54) and LFA-3 (CD58) following CMV infection in vitro. We investigated whether the induction of adhesion molecules by CMV was a direct viral effect or secondary to cytokine induction. Cytokines known to up-regulate ICAM-1, such as TNFalpha or IL-1beta, were not detected in the supernatants of infected fibroblasts, and neutralizing antibodies against these cytokines did not abrogate the induction of either ICAM-1 or LFA-3 by CMV. Infected cell supernatants had increased levels of IL-6, IL-8 and IFNbeta however, the addition of recombinant forms of these cytokines did not affect adhesion molecule expression. Neither virus-free infected cell supernatants nor UV-inactivated virus up-regulated adhesion molecules, demonstrating that the induction of ICAM-1 and LFA-3 by CMV was a direct effect requiring infectious virus. Effective antiviral treatment with ganciclovir or foscarnet accentuated rather than abrogated the up-regulation of adhesion molecules, suggesting that CMV immediate early/early gene expression, which is not blocked by such treatment, was responsible for the adhesion molecule induction. Thus, despite effective antiviral therapy in the transplant recipient, CMV infected cells may continue to provide a focus of proinflammatory activity, which could contribute to immunopathology and/or accentuate graft rejection or graft-versus-host disease in vivo.
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PMID:Cytomegalovirus induced up-regulation of LFA-3 (CD58) and ICAM-1 (CD54) is a direct viral effect that is not prevented by ganciclovir or foscarnet treatment. 890 Mar 10

Three mAb (R2/60, S7 and 1B11) were used to study the expression of murine CD43 on peripheral T cells and intestinal intraepithelial lymphocytes (IEL) from normal mice, and from mice during acute graft versus host disease (GVHD). In the spleen, essentially all T cells expressed the R2/60 and S7 antigens, whereas the 1B11 antigen was expressed on about half of the CD8(+) cells and approximately 15% of CD4(+) T cells. Interestingly, a significant proportion of resting splenic B cells expressed the 1B11 and R2/60 antigens, but not the S7 antigen. The majority of IEL expressed R2/60 antigen; however, the S7 and 1B11 markers were differentially expressed on CD8alpha, CD8beta, TCRalphabeta and TCRgammadelta cells. Immunoprecipitation and Western blotting analyses identified characteristic 115 and 130 kDa reactive components from IEL lysates with mAb S7 and 1B11 respectively, and reactivity to both molecular entities by mAb R2/60. During acute intestinal GVHD induced by injecting CB6F(1) athymic nude mice with spleen cells from C57BL/6 enhanced-green fluorescent protein transgenic mice, 80-90% of donor T cells in the intestine epithelium expressed all CD43 isoforms; however, the level of expression of the 130 kDa CD43 antigen increased significantly and the level of the 115 kDa antigen decreased on GVHD donor T cells compared to cells at the time of transfer. Using EL4 cells, a similar shift in the expression of CD43 isoforms occurred experimentally following treatment with neuraminidase, suggesting that the type of CD43 isoform expressed on T cells is strongly influenced by conditions which affect membrane charge. The significance of these findings for intestinal immunopathology is discussed.
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PMID:Differential expression of CD43 isoforms on murine T cells and their relationship to acute intestinal graft versus host disease: studies using enhanced-green fluorescent protein transgenic mice. 1050 83

Intestinal immunopathology was studied after allogeneic stem cell transplantation (SCT) in a common clinical setup in 20 children with malignant (n=17) or nonmalignant diseases (n=3) receiving grafts from siblings (7) and unrelated donors (13). In all, 19 had total body irradiation. Duodenal biopsies at 6 and 12 weeks post transplant were evaluated by histology, immunohistochemistry, and ISEL for the detection of T-lymphocytes, inflammatory cytokines, proliferation, and apoptosis. The controls were 12 healthy children and three patients with proven intestinal graft-versus-host disease. An increased rate of apoptosis and proliferation with upregulated expression of HLA-DR antigen was detected up to 3 months post transplant in the SCT patients, even in those with a histologically normal small intestine. A low level of IFNgamma and TNFalpha was observed in the lamina propria. The initial low density of gammadelta-positive T cells had recovered to normal by the time of the second endoscopy at 12 weeks post transplant. We conclude that inflammatory activity and T cell infiltration detected by immunohistochemistry may not belong to the 'normal' recovery of the small intestine after SCT. Increased cell turnover in the intestinal crypts continues until 3 months after SCT, suggesting either an unexpectedly long-lasting effect of transplant-related toxicity or, preferably, an ongoing subclinical alloreactive process, also present in the patients without intestinal symptoms.
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PMID:Increased cell turnover, but no signs of increased T-cell infiltration or inflammatory cytokines in the duodenum of pediatric patients after allogeneic stem cell transplantation. 1517 Jan 68

The butyric acid derivative, 2-(4-morpholynl) ethyl butyrate hydrochloride (MEB), has been reported to induce antigen-specific T cell unresponsiveness and to block T cell-mediated graft-versus-host disease. As a potential therapeutic agent, it was important to determine the effects of MEB on other cells that contribute to immunopathology. Accordingly, we tested the effects of MEB on macrophage functions. MEB did not affect macrophage viability, phagocytic activity, or the activation-induced up-regulation of molecules associated with antigen presentation: MHC-II, CD86, CD40, or ICAM-1. However, MEB potently inhibited activation-induced production of inflammatory mediators, including tumor necrosis factor-alpha (TNF-alpha), IL-6, chemokine CCL2 and nitric oxide (NO). MEB inhibited the induction of NO synthase (NOS2), which is necessary for inducible NO, and inhibited nuclear translocation of NFkappaB, suggesting that MEB interferes with the signaling pathway involved in NOS2 induction. Thus, while inducing specific T cell unresponsiveness, MEB also exerts anti-inflammatory activity by acting on macrophages to suppress production of cytokines and NO.
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PMID:Macrophage production of inflammatory mediators is potently inhibited by a butyric acid derivative demonstrated to inactivate antigen-stimulated T cells. 1525 Nov 19


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