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)

When graft-versus-host (GVH) disease affects the liver, it is characteristically the bile ducts which are involved, infiltrated by lymphocytes. To characterize this process further, and to determine whether there were any antigenic changes in the bile ducts, we stained 9 liver biopsies involved by GVH disease, 10 non-GVH biopsies that had a prominent portal lymphocytic component, and 8 biopsies taken incidentally at surgery for noninflammatory liver disease with epithelial membrane antigen, AE-3, AE-1, a keratin cocktail, keratin 19, CD45RO (UCHL-1), CD43 (Leu-22), CD20 (L26), vimentin, and LN-3. The infiltrating lymphocytes were T cells (CD45RO+, CD43+, CD20-) which variably expressed LN-3. The bile ducts were positive for the keratin cocktail, AE-1, AE-3, and keratin-19, but only occasionally positive for EMA and LN-3. There was no significant difference in the staining patterns of either the bile duct cells or lymphocytes between the three groups. With the antibodies that we used, there does not appear to be a significant difference in the antigenic phenotype of the bile ducts in GVH as compared to normal or reactive livers.
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PMID:Phenotype of bile ducts and infiltrating lymphocytes in graft-versus-host disease. 768 95

Graft-versus-host disease (GVHD) is a life threatening complication that may occur following allogenic bone marrow transplantation (BMT) in the patients with aplastic anemia, leukemia or genetic immunodeficiency. It has been known that GVHD occurs approximately 70% of recipients of BMT in western countries but no definite incidence has been reported in Korea. In our St. Mary's Hospital, GVHD occurs in about 30% of BMT recipients. Histopathologically the acute phase skin shows diffuse lymphocytic infiltrates in the upper dermis with extensive exocytosis. Scattered throughout the epidermis are many degenerated keratinocytes, which are often associated with one or more satellite lymphocytes (satellite cell necrosis). In the chronic phase, acanthosis, eosinophilic keratinocytes resembling colloid bodies and mononuclear cell infiltrates in the upper dermis are noted. We reviewed 5 cases of acute GVHD and 6 cases of chronic GVHD. All patients received allogenic BMT from Jan. 1, 1992 to July 1, 1993. Ten patients were male and one was female. The mean age was 34 (20-70). The pathologic diagnosis was 3 cases of CML, 2 of ALL, 2 of AML (FAB M2), 2 of aplastic anemia, 1 of CLL and 1 of AML (FAB M5). The interval from BMT to GVHD varied from 14 days to 4 years (median 220 days). The skin and GI tract were involved in all eleven cases. Ten cases were histologically proven by skin biopsies, and two cases by salivary gland and colonic biopsies, respectively. The histological findings of the skin, salivary gland and colonic biopsieds were described. Immunohistochemical stain of the skin was done using CD4, CD8, HLA DR and Leu 7 antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Graft-versus-host disease--clinical and pathological analysis of 11 biopsy proven cases. 770 86

Minor histocompatibility antigens (mHags) are involved in the induction of graft-versus-host disease (GVHD) after HLA-identical bone marrow transplantation. Previously, we isolated a series of HLA-A*0201-restricted cytotoxic T-cell (CTL) clones specific for the same mHag HA-1 from peripheral blood of three unrelated patients who were suffering from GVHD. We have now analyzed the composition of the T-cell receptor (TCR) V regions of 12 of these mHag HA-1-specific HLA-A*0201-restricted CTL clones by DNA sequencing of the alpha and beta chains. Of these 12 clones, derived from three unrelated individuals, five independent TCR alpha V- and beta V-region sequences were established. The TCR alpha chains were composed of varying TCR alpha V and TCR alpha J genes with no obvious similarities in structure in the N regions. However, the TCR beta chains all used the TCR beta V6S9 gene segment, and showed remarkable similarities within the N-D-N regions; ie, three independent beta-chain sequences (originating from donors Ha and Gy) shared a leucine/valine amino acid pair, whereas the other two (originating from donors Ha and Wi) shared a serine/threonine pair, all at positions 99 and 100 of the TCR beta V region. In conclusion, the TCR analysis of HA-1 mHag-specific CTL clones has shown that the HA-1 mHag/HLA-A*0201 complex selects for highly similar TCR beta V regions.
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PMID:Interindividual conservation of T-cell receptor beta chain variable regions by minor histocompatibility antigen-specific HLA-A*0201-restricted cytotoxic T-cell clones. 772 78

The role of TNF in the expression of GVHD and GVHD-related immunodeficiency was studied in a well-established murine GVHD model of bone marrow transplantation across minor histocompatibility barriers (B10.BR-->GBA/J) both in vitro and in vivo. Splenocytes from animals with GVHD profoundly inhibited the proliferation of normal spleen cells in response to a wide range of stimuli in an MHC-nonrestricted fashion. Neutralizing mAbs to TNF reversed the ability of splenocytes from animals with GVHD to suppress the proliferation of normal splenocytes stimulated by the mitogen concanavalin A. Addition of rTNF enhanced the degree of suppression. This reversal was similar to that previously reported for IFN gamma and leucine methyl ester treatment of the GVHD populations. All three components are necessary for suppression to occur because addition of rTNF to cultures in which suppression had been reversed by anti-IFN gamma or leucine methyl ester treatment did not reconstitute suppression. Neutralization of endogenous TNF production in vivo resulted in an amelioration of clinical GVHD, but neutralization of endogenous IFN gamma resulted in a more severe course. However, in vivo neutralization of either TNF or IFN gamma post-BMT resulted in a decreased ability of splenocytes from animals with GVHD to suppress mitogen responses but did not affect the generation of the suppressor cell population. These findings support multiple roles for TNF and IFN gamma in the pathophysiology of GVHD, including terminal cellular differentiation and/or regulation of effector cell function.
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PMID:The role of tumor necrosis factor and interferon gamma in graft-versus-host disease and related immunodeficiency. 831 May 20

Recent studies have suggested that dipeptidyl peptidase I (DPPI) is the major post-translational processing enzyme responsible for generating activated myeloid and lymphoid granule serine proteases. The current studies assessed the relative levels of DPPI and granzyme A (BLT esterase) in B6 anti-H-2d-specific CTL generated in mixed lymphocyte cultures (in vitro-activated CTL), by infusion of B6 spleen cells into irradiated H-2d mice (graft-vs-host, GVH CTL) or by 1 degree and 2 degrees peritoneal immunization of B6 mice with P815 (H-2d) cells (PE CTL). In contrast to low levels of DPPI activity in unstimulated CD4+ spleen T cells, both unstimulated CD8+ spleen T cells and in vitro-activated CTL populations were several-fold enriched in DPPI activity, while PE CTL and GVH CTL expressed even higher levels of DPPI. Depletion of DPPI-enriched cells by treatment with Leu-Leu-OMe resulted in loss of cytolytic effector function from each CTL population. However, PE CTL and GVH CTL were more sensitive to the toxicity of Leu-Leu-OMe than were in vitro-activated CTL. While standard BLT esterase assays detected much higher levels of this serine protease activity in GVH CTL or in vitro-activated CTL than in PE CTL, levels of BLT esterase activity significantly above the basal levels present in unstimulated CD8+ or CD4+ T lymphocytes were found in association with immunoreactive granzyme A in lysates of PE CTL. In both PE CTL and in vitro-activated CTL, DPPI and BLT esterase activity co-localized in the granule fraction of cell lysates, and similar percentages of total cellular BLT esterase and DPPI were exocytosed upon cross-linking of surface CD3. Thus, both in vivo- and in vitro-activated CTL were found to possess functional granules containing readily detectable albeit somewhat different levels of DPPI and granzyme A activity.
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PMID:Dipeptidyl peptidase I is enriched in granules of in vitro- and in vivo-activated cytotoxic T lymphocytes. 849 87

L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) is a lysosomotropic agent that selectively kills cytotoxic T cells and their precursors, natural killer cells, and monocytes but not helper T cells or other cells of hematopoietic origin. In this study, the effects of treatment of bone marrow and peripheral blood buffy coat with Leu-Leu-OMe on the outcome of allogeneic marrow transplantation were studied in several canine models. Whereas incubation of autologous marrow with Leu-Leu-OMe had no adverse effects on subsequent engraftment, incubation of marrow from dog leukocyte antigen (DLA)-identical littermates resulted in a high rate of graft failure. Previous studies have demonstrated that the addition of peripheral blood buffy coat allows engraftment of unrelated DLA-nonidentical marrow, and in this study we found that incubation of buffy coat with Leu-Leu-OMe did not alter this graft promoting effect. In a final experiment it was demonstrated that incubation of both marrow and peripheral blood buffy coat did not prevent the development of graft-versus-host disease in recipients of marrow from DLA-haploidentical littermates. In considering the eventual application of Leu-Leu-OMe in the clinic, these results are less encouraging than those previously reported using murine models.
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PMID:Studies of the use of L-leucyl-L-leucine methyl ester in canine allogeneic marrow transplantation. 851 9

Cytomegalovirus (CMV) infection has been associated with graft rejection in solid organ transplantation and with graft-versus-host disease in marrow transplantation. We hypothesized that CMV-infected endothelial cells play an important role in the rejection process, because of their strategic localization at the interface with the host immune system and their ability to modulate T cell function. To study the effect of CMV infection on cell-mediated cytotoxicity against endothelial cells, peripheral blood mononuclear cells (MNC) were incubated with CMV-infected umbilical vein endothelial cells (CMV-UVEC) or mock-infected controls (M-UVEC) and lysis measured by [3H]leucine release. MNC lysed only CMV-UVEC to a maximum of 23% at E:T 20:1. Lysis was not affected by CD3+ cell depletion, but was abolished by CD16+ cell depletion, indicating that NK cells were the effectors. The kinetics of the NK-mediated lysis of CMV-UVEC paralleled the time course of CMV antigen expression. Furthermore, ganciclovir treatment of CMV-UVEC cultures decreased both specific antigen synthesis and NK-mediated lysis. This indicated that NK might recognize either a viral antigen or a cellular antigen modulated by CMV infection. Treatment of CMV-UVEC with F(ab)2 fragments of human polyclonal anti-CMV antibodies failed to inhibit NK cytotoxicity. In contrast, F(ab)2 fragments of MB40.5, a murine MAb reactive with a conserved epitope on the human MHC class I, significantly decreased lysis, proving that NK lysis of CMV-UVEC is an MHC class I-dependent function. To determine whether CMV-UVEC lysis was dependent solely on upregulation of MHC class I, MNC were incubated with CMV-UVEC mixed with uninfected UVEC. There was no competition for NK-target recognition sites, indicating that NK lysis required an interaction with an MHC class I antigen modified by viral infection. Antibodies against IFN-alpha or -beta did not block NK cytotoxicity against CMV-UVEC. Our findings provide a working frame for further evaluation of cellular immune responses to CMV infection.
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PMID:NK recognition of cytomegalovirus-infected endothelial cells depends on viral replication and MHC class I expression. 882 29

In a study of 523 normal subjects of differing ethnic groups, including 189 South American Indians, we have described novel hybridization pattern corresponding to 22 potentially new HLA-B locus alleles. Three of these alleles were subtypes of B35. The locally, assigned alleles, B-3504v, B-3505v, and B-3508v have been sequenced and were officially designated as B*3512, B*3517, and B*3518, respectively. In addition, we determined the nucleotide sequence of another new variant, locally designated B-3509.2. B*3517, was found in 3 individuals (2 Hispanic, 1 Caucasian), it differs from B*3505 by 3 nucleotide substitutions that lead to changes in residues 94, 95, and 103. B*3517 differs from B*3501 in residues 97 and 103. B*3518 was found in 7 South American Indian individuals (6 of 124 Toba Indians, 1 of 18 Pilaga Indians). It differs from B*3509 by 2 silent nucleotide substitutions and by one nonsynonymous substitution in codon 156 (Arg-->Leu). B*3512 differs from B*3504 by 3 nucleotides, one of them leading to a substitution in residue 103 (Val-->Leu). B*3509 was observed in 3 individuals from the Wichi tribe. The nucleotide sequence of one of these was determined and was found to differ from B*35091 by two synonymous nucleotide substitutions. The distinguishing amino acid substitutions in residues 95, 97, and 156 contribute to the structure of specificity pockets F, C, and E, and D and E respectively, therefore, it is possible that some of the new alleles may have different peptide binding profiles. It has been shown that differences at residue 156 may elicit different allorecognition and mediate graft-versus-host disease and rejection in bone marrow transplantation. The mechanisms for the generation of these novel alleles may involve gene conversion events in which short exon-3 segments from the common Native American alleles B*4002 or B*4801 were inserted in HLA-B35 backbone structures. The novel allele B*3518 is closely related to B*35092 and to B*3508. Two alternative hypotheses for its generation can be suggested, the most plausible one would involve B*35092, the putative progenitor of B*3518, since both alleles are prevalent in the same Indian tribes.
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PMID:Novel HLA-B35 subtypes: putative gene conversion events with donor sequences from alleles common in native Americans (HLA-B*4002 or B*4801). 912 72

CD31 gene polymorphisms are implicated in the pathogenesis of graft-versus-host disease (GvHD) following haematopoietic stem cell transplantation (HST). We investigated the influence of CD31 genotype on the incidence of GvHD following HST from an human leukocyte antigen (HLA)-identical sibling donor. Donor and recipient CD31 codons 125, 563 and 670 DNA polymorphisms were determined in 85 cases of HLA identical sibling HST from two transplant centres. A correlation between CD31 genotype and acute GvHD was considered significant if observed in patients from both transplant centres independently. A strong correlation was identified between donor CD31 codon 125 genotype and the incidence of acute GvHD. Acute GvHD grades II-IV occurred in 27 of 46 (59%) recipients with a CD31 codon 125 leucine / valine heterozygous donor compared to nine of 39 (23%) recipients with a CD31 codon 125 homozygous donor (P=0.0019, relative-risk 2.45, 95% confidence interval 1.3-4.5). This correlation was significant in patients from both transplant centres (P=0.015 and P=0.019). We suggest that CD31 genotype may influence the function of donor-derived leukocytes and may be informative when there is a choice of comparable donors.
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PMID:Donor CD31 genotype and its association with acute graft-versus-host disease in HLA identical sibling stem cell transplantation. 1590 74

The last 10 years have witnessed the identification of a new class of intracellular pattern-recognition molecules--the nucleotide-binding domain and leucine-rich repeat-containing family (NLR). Members of this family garnered interest as pattern-recognition receptors able to trigger inflammatory responses against pathogens. Many studies support a pathogen-recognition function for human NLR proteins and shed light on their role in the broader control of adaptive immunity and various disease states. Other evidence suggests that NLRs function in processes unrelated to pathogen detection. Here we discuss recent advances in our understanding of the biology of the human NLR proteins and their non-pathogen-recognition function in tissue homeostasis, apoptosis, graft-versus-host disease and early development.
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PMID:NLR functions beyond pathogen recognition. 2124 3


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