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)

This study was purposed to investigate the dynamic change of clonal proliferation of T cell receptor V subfamilies in peripheral blood of patients received allo-hematopoietic stem cell transplantation (allo-HSCT) and to analyze the relationship between T cell clonal proliferative changes and GVHD. The peripheral blood mononuclear cell samples from 70 cases (17 GVHD patients) undergoing allo-PBCST patients were detected for CDR3 (complementarity determining region 3 repertoire analysis of T cell receptor Vbetagene) using reverse-transcriptase-polymerase chain reaction (RT-PCR). The products were further analyzed by genescan to identify T cell clonality. The results showed that the patients of HSCT generally passed through a transformation from monoclone to polyclone. At day 60 - 90 after HSCT, half of the cases were monoclonal and the remainders were polyclonal. After 120 days, most of patients without GVHD transferred into polyclones, however, patients with GVHD remained monoclonal after one year because of immunosuppressive agents and GVHD itself. The peripheral blood of GVHD patients mainly expressed monoclone/biclone at the time of target organ damage conspicuously, after medication intervention, partial monoclone or bioclone expressed TCR Vbeta subfamilies were diverted to polyclonal expression. It is concluded that the T cells present clonal proliferation and T cell receptors are prone to be used when patients are in earlier period of transplantation or with GVHD especially. The expression of TCR Vbeta subfamilies can return to normal polycloning along with the recovery of hematopoiesis and immunity in patients.
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PMID:[Clonal kinetic proliferative change of TCR Vbeta subfamilies in peripheral blood of patients transplanted with allogeneic hematopoietic stem cells and its relation to GVHD]. 1770 6

Regulatory T cells (Tregs) prevent graft-versus-host disease (GvHD) by inhibiting the proliferation and function of conventional T cells (Tcons). However, the impact of Tregs on T-cell development and immunity following hematopoietic cell transplantation (HCT) is unknown. Using a murine GvHD model induced by Tcons, we demonstrate that adoptive transfer of Tregs leads to (1) abrogration of GvHD, (2) preservation of thymic and peripheral lymph node architecture, and (3) an accelerated donor lymphoid reconstitution of a diverse TCR-Vbeta repertoire. The resultant enhanced lymphoid reconstitution in Treg recipients protects them from lethal cytomegalovirus (MCMV) infection. By contrast, mice that receive Tcons alone have disrupted lymphoid organs from GvHD and remain lymphopenic with a restricted TCR-Vbeta repertoire and rapid death on MCMV challenge. Lymphocytes from previously infected Treg recipients generate secondary response specific to MCMV, indicating long-term protective immunity with transferred Tregs. Thymectomy significantly reduces survival after MCMV challenge in Treg recipients compared with euthymic controls. Our results indicate that Tregs enhance immune reconstitution by preventing GvHD-induced damage of the thymic and secondary lymphoid microenvironment. These findings provide new insights into the role of Tregs in affording protection to lymphoid stromal elements important for T-cell immunity.
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PMID:The impact of regulatory T cells on T-cell immunity following hematopoietic cell transplantation. 1791 43

Enhanced cyclosporine-A (CsA) sensitivity of umbilical cord blood (CB) CD4(+) T cells may contribute to the lower incidence of graft-versus-host disease (GVHD) after mismatched CB transplantation. Interleukin (IL)-15, an IL-2 like gamma-chain signaling cytokine, may bypass CsA inhibition and play an important role in GVHD pathogenesis. The present study examines CsA sensitivity of IL-15-driven CB CD4(+) T cell survival, activation and proliferation, comparing adult peripheral blood (APB) CD4(+) T cell responses. We establish that (1) resting CB CD4(+) T cells were more susceptible to CsA-induced cell death than their adult counterpart; (2) IL-15 help support the survival of resting CB CD4(+) T cell under the influence of CsA, though to a lesser degree that observed in adults; (3) higher CsA sensitivity of CD25 up-regulation following TCR activation was observed in CB but more readily counteracted by IL-15 compared to adults; (4) IL-15-driven proliferation of TCR-activated CD4(+) T cells was more susceptible to CsA inhibition than corresponding adults; and (5) TCR-activated CB CD4(+) T cells surviving high dose CsA (5 microg/ml) in IL-15-supplemented cultures expressed significantly lower percentages of CD45RO(-)/CD25(+) subsets compared to corresponding APB. Taken together, the differential CsA sensitivity and IL-15 response between CB and APB CD4(+) T cells may contribute to the lessened GVHD severity in the setting of CB transplantation.
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PMID:Differential cyclosporin-A sensitivity on survival and activation of umbilical cord and adult peripheral blood CD4+ T cells. 1800 64

Keratinocyte growth factor (KGF) has been shown to reduce the incidence and severity of graft-versus-host disease by prevention of epithelial damage and by modulating alloreactivity. Since regulatory T cells (Treg) play a crucial role in immune modulation, we evaluated the effects of exogenous KGF on peripheral CD4(+)Foxp3(+) Treg and the generation of Treg in the thymus of normal mice. A 3-day course of KGF induced a rapid selective increase in the number of highly suppressive CD4(+)Foxp3(+) Treg. Blood Treg numbers remained elevated for >2 mo, but the frequency normalized after 2 wk due to a concomitant increase in CD4(+)Foxp3(-) T cells. Analysis of single joint TCR excision circles frequency and Ki-67 expression in peripheral blood Treg showed that the early selective increase of Treg was predominantly accounted for by peripheral expansion. Thymectomy before KGF administration did not affect the early selective increase of Treg but abrogated the late increase in CD4(+) T cell numbers, thereby showing its dependence on thymic output. Collectively, these results show that KGF induces an increase in blood CD4(+)Foxp3(+) Treg numbers via two independent mechanisms. First by selective peripheral expansion of Treg and thereafter by enhanced thymic output of newly developed Treg.
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PMID:Keratinocyte growth factor induces expansion of murine peripheral CD4+Foxp3+ regulatory T cells and increases their thymic output. 1802 86

Double-negative (DN) regulatory T cells (Tregs) are specialized T lymphocytes involved in the down-modulation of immune responses, resulting in allotolerance after allogeneic haematopoietic stem cell transplantation (HSCT). Most of the properties of DN Tregs were identified in murine models, including the unique ability to suppress alloreactive syngeneic effector T cells in an antigen-specific manner via Fas/Fas-ligand interactions. We investigated the behaviour of DN Tregs following human allogeneic HSCT with regard to occurrence of graft-versus-host disease (GvHD) and restoration of T-cell receptor repertoire in a cohort of 40 patients. The frequency of DN Tregs and CD4/CD8 TCR repertoire was measured serially and at the time of diagnosis of GvHD by flow cytometry. Analysis demonstrated a positive correlation between degree of alloreactivity, as measured by grade of GvHD, and the number of variable beta chain (Vbeta) family expansions in both T-cell populations. We also found that a deficiency of DN Tregs was associated with an increased number of Vbeta family expansions, and most importantly, with the occurrence of GvHD. All individuals who demonstrated more than 1% DN Tregs did not develop GvHD, providing evidence that DN Tregs participate in peripheral tolerance to prevent GvHD when expanded after allogeneic HSCT.
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PMID:Double-negative regulatory T cells induce allotolerance when expanded after allogeneic haematopoietic stem cell transplantation. 1831 70

Three cases of the so-called variant of primary cutaneous CD30+ anaplastic large cell lymphoma (ALCL) are presented. All patients were males aged 52, 59, and 78 years old; they had a solitary cutaneous tumor nodule. Their sites included the axilla, thigh, and shoulder. There was no extracutaneous involvement. Microscopically, the tumors were composed of small cells with irregular nuclei that were immunohistochemically positive for CD3, CD5, CD7, and CD30 and negative for B-cell markers; there was focal ALK-1 positivity in 1 case. Two cases had CD4+/CD8-phenotype, while the remaining one exhibited a CD4-/CD8+ immunoprofile. Fhedium to large CD30+ cells were rarely found scattered in the infiltrate. Monoclonal TCR gamma gene rearrangement was detected in 2 cases and rearrangement of IgH (lineage infidelity) was in one case. The tumors were surgically removed in all the patients. Two patients were alive and well 4 and 6 years after surgery, without evidence of cutaneous and extractaneous involvement (including the ALK+ patient). The third patient experienced several relapses of the skin tumor and developed axillary and inguinal lymph node involvement. Chemotherapy was performed and finally the patient underwent allogenic bone marrow transplantation; he died 3 years after the original diagnosis due to acute graft-versus-host disease and sepsis.
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PMID:[Small-cell variant of CD30+ -anaplastic large-cell lymphoma of the skin]. 1854 Apr 41

Following allogeneic blood and marrow transplantation (BMT), mature donor T cells can enhance engraftment, counteract opportunistic infections, and mount graft-versus-tumor (GVT) responses, but at the risk of developing graft-versus-host disease (GVHD). With the aim of separating the beneficial effects of donor T cells from GVHD, one approach would be to selectively deplete subsets of alloreactive T cells in the hematopoietic cell inoculum. In this regard, TCR Vbeta repertoire analysis by CDR3-size spectratyping can be a powerful tool for the characterization of alloreactive T-cell responses. We investigated the potential of this spectratype approach by comparing the donor T-cell alloresponses generated in vitro against patient peripheral blood lymphocytes (PBLs) with those detected in vivo posttransplantation. The results indicated that for most Vbeta families that exhibited alloreactive CDR3-size skewing, there was a robust overlap between the in vitro antipatient and in vivo spectratype histograms. Thus, in vitro spectratype analysis may be useful for determining the alloreactive T-cell response involved in GVHD development and, thereby, could serve to guide select Vbeta family depletion for designer transplants to improve outcomes.
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PMID:Overlap between in vitro donor antihost and in vivo posttransplantation TCR Vbeta use: a new paradigm for designer allogeneic blood and marrow transplantation. 1884 Jul 24

Natural killer T (NKT) cells, a distinct subset of T cells that recognize glycolipids on CD1d molecules, express both TCR and NK receptors and are critical in regulating various immune responses by modulating the Th1/Th2 balance. Upon activation, NKT cells produce large amounts of IL-4 and IFN-gamma, resulting in the enhancement or inhibition of immune responses. Recent studies have shown that NKT cells are heterogeneous in terms of the expression of a specific Valpha chain of TCR (Valpha14-Jalpha18 in mice and Valpha24-JalphaQ in humans) and reactivity against the glycolipid alpha-galactosylceramide (alpha-GalCer). Accordingly, NKT cells are classified into type I (invariant) and type II (non-invariant) cells in mice and humans. Although the functional roles of type I NKT cells are well characterized in various immune diseases, little is known regarding the function of type II NKT cells. Recent study has demonstrated that type II NKT cells in donor bone marrow play protective roles in graft-versus-host disease (GVHD), in which the complicated immunologic processes are involved. In this review, we discuss the pathogenesis of GVHD and the distinct functions of type II NKT cells in the development of GVHD.
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PMID:Role of type II NKT cells in the suppression of graft-versus-host disease. 1902 48

T cell recognition of minor histocompatibility antigens (mHags) underlies allogeneic immune responses that mediate graft-versus-host disease and the graft-versus-leukemia effect following stem cell transplantation. Many mHags derive from single amino acid polymorphisms in MHC-restricted epitopes, but our understanding of the molecular mechanisms governing mHag immunogenicity and recognition is incomplete. Here we examined antigenic presentation and T-cell recognition of HA-1, a prototypic autosomal mHag derived from single nucleotide dimorphism (HA-1(H) versus HA-1(R)) in the HMHA1 gene. The HA-1(H) peptide is restricted by HLA-A2 and is immunogenic in HA-1(R/R) into HA-1(H) transplants, while HA-1(R) has been suggested to be a "null allele" in terms of T cell reactivity. We found that proteasomal cleavage and TAP transport of the 2 peptides is similar and that both variants can bind to MHC. However, the His>Arg change substantially decreases the stability and affinity of HLA-A2 association, consistent with the reduced immunogenicity of the HA-1(R) variant. To understand these findings, we determined the structure of an HLA-A2-HA-1(H) complex to 1.3A resolution. Whereas His-3 is accommodated comfortably in the D pocket, incorporation of the lengthy Arg-3 is predicted to require local conformational changes. Moreover, a soluble TCR generated from HA-1(H)-specific T-cells bound HA-1(H) peptide with moderate affinity but failed to bind HA-1(R), indicating complete discrimination of HA-1 variants at the level of TCR/MHC interaction. Our results define the molecular mechanisms governing immunogenicity of HA-1, and highlight how single amino acid polymorphisms in mHags can critically affect both MHC association and TCR recognition.
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PMID:Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition. 1923 24

Low severity of GVHD, substantial graft vs tumor (GVT) and slow development of protective immunity are well-documented features of cord blood transplants (CBT). We have evaluated the immune reconstitution of adult recipients of single-unit CBT supported by the coinfusion of third party donor (TPD) mobilized hematopoietic stem cells (MHSC), a procedure-'dual CB/TPD-MHSC transplant'-that results in early recovery of circulating granulocytes, high rates of CB engraftment and full chimerism. Cumulative recovery of natural killer and B cells at or above the median values of normal controls were 1.0 and 0.76 by the sixth and ninth months. Recovery of T cells was much slower, naive cells lagging behind those of memory and effector (committed) immunophenotypes. Serial analyses of signal joint TCR excision circles showed a general pattern of very low levels by the third month after CBT, followed by recovery to levels persistently similar or higher than those observed before transplantation and in normal controls. Our results are consistent with the clinical observations of substantial GVT effect together with low incidence of serious GVHD and slow development of protective immunity and suggest that thymic function contributes substantially to the recovery of T-cell populations in adults receiving dual CB/TPD-MHSC transplants.
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PMID:Immune reconstitution after cord blood transplants supported by coinfusion of mobilized hematopoietic stem cells from a third party donor. 1925 33


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