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)

Graft-versus-host disease (GVHD) is caused by alloreactive donor T cells that trigger host tissue injury. GVHD develops over weeks or months, but how this immune response is maintained over time is unknown. In mouse models of human GVHD, we identify a new subset of postmitotic CD44(lo)CD62L(hi)CD8(+) T cells that generate and sustain all allogeneic T-cell subsets in GVHD reactions, including central memory, effector memory and effector CD8(+) T cells, while self-renewing. These cells express Sca-1, CD122 and Bcl-2, and induce GVHD upon transfer into secondary recipients. The postmitotic CD44(lo)CD62L(hi)CD8(+) T cells persist throughout the course of GVHD, are generated in the initial phase in response to alloantigens and dendritic cells and require interleukin-15. Thus, their long life, ability to self-renew and multipotentiality define these cells as candidate memory stem cells. Memory stem cells will be important targets for understanding and influencing diverse chronic immune reactions, including GVHD.
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PMID:Host-reactive CD8+ memory stem cells in graft-versus-host disease. 1633 66

Rapamycin prevention of murine graft-versus-host disease (GVHD) is associated with a shift toward Th2- and Tc2-type cytokines. Recently, we found that use of rapamycin during ex vivo donor Th2 cell generation enhances the ability of adoptively transferred Th2 cells to prevent murine GVHD. In this study, using a method, without antigen-presenting cells, of T-cell expansion based on CD3,CD28 costimulation, we evaluated whether (1) rapamycin preferentially promotes the generation of Th2/Tc2 cells relative to Th1/Tc1 cells, (2) rapamycin-generated T-cell subsets induce cytokine skewing after allogeneic bone marrow transplantation (BMT), and (3) such in vivo cytokine skewing is sensitive to post-BMT rapamycin therapy. Contrary to our hypothesis, rapamycin did not preferentially promote Th2/Tc2 cell polarity, because rapamycin-generated Th1/Tc1 cells secreted type I cytokines (interleukin [IL]-2 and interferon-gamma) did not secrete type II cytokines (IL-4, IL-5, IL-10, or IL-13) and mediated fasL-based cytolysis. Rapamycin influenced T-cell differentiation, because each of the Th1, Th2, Tc1, and Tc2 subsets generated in rapamycin had increased expression of the central-memory T-cell marker, L-selectin (CD62L). Rapamycin-generated Th1/Tc1 and Th2/Tc2 cells were not anergic but instead had increased expansion after costimulation in vitro, increased expansion in vivo after BMT, and maintained full capacity to skew toward type I or II cytokines after BMT, respectively; further, rapamycin-generated Th1/Tc1 cells mediated increased lethal GVHD relative to control Th1/Tc1 cells. Rapamycin therapy after BMT in recipients of rapamycin-generated Th1/Tc1 cells greatly reduced Th1/Tc1 cell number, greatly reduced type I cytokines, and reduced lethal GVHD; in marked contrast, rapamycin therapy in recipients of rapamycin-generated Th2/Tc2 cells nominally influenced the number of Th2/Tc2 cells in vivo and did not abrogate post-BMT type II cytokine skewing. In conclusion, ex vivo and in vivo usage of rapamycin may be used to modulate the post-BMT balance of Th1/Tc1 and Th2/Tc2 cell subsets.
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PMID:Ex vivo rapamycin generates Th1/Tc1 or Th2/Tc2 Effector T cells with enhanced in vivo function and differential sensitivity to post-transplant rapamycin therapy. 1692 May 56

We determined the alleles of five polymorphic molecules including HA-1 and four adhesion molecules for 106 patients transplanted with HLA-identical stem cell grafts and investigated the association of mismatches as correlates of relapse and graft-versus-host disease (GVHD). All 106 recipients underwent stem cell transplantation (SCT) after myeloablative conditioning between 1985 and 2002. Risk status of disease at SCT was standard (n=63) and high (n=42). After SCT, 36, 49 and 33 developed acute GVHD, chronic GVHD and relapsed, respectively. Our patients relapsed at rates of 16.7 and 38.6% with one or more and without incompatibilities (P=0.013). The relapse rates of patients with CD62L, CD31 codon 563, CD31 codon 125, HA-1 and CD49b incompatibilities were 5.9, 11.8, 15.4, 16.0 and 33.3%, respectively. The frequency of acute GVHD did not differ regardless of incompatibilities. In standard-risk group, the accumulated relapse rates of 19 and 44 patients with and without minor histocompatibility antigen incompatibility were 22% and unexpectedly 66%, respectively (P=0.02). The probability of 12-year survival was 88% in the former and 66% in the latter patients (P=0.03). Our data suggest that incompatibility of CD62L, CD31 codon 563 and CD31 codon 125 contributes to a graft-versus-leukemia effect rather than to GVHD, resulting in prolonged survival after HLA-identical SCT.
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PMID:Mismatch of minor histocompatibility antigen contributes to a graft-versus-leukemia effect rather than to acute GVHD, resulting in long-term survival after HLA-identical stem cell transplantation in Japan. 1698 Sep 88

We previously found that CD8 T cells from IFN-gamma gene knockout (GKO) donors induce more severe lethal GVHD compared with CD8 T cells from wild-type (WT) donors in fully MHC-mismatched strain combinations. In this study, we investigated the mechanisms by which IFN-gamma inhibits GVHD in a parent --> F1 (B6 --> B6D2F1) allogeneic HCT (allo-HCT) model. IFN-gamma was strongly protective against GVHD in this parent --> F1 haplotype-mismatched allo-HCT model. Irradiated B6D2F1 mice that received GKO B6 CD4-depleted splenocytes developed lethal GVHD with severe lung and liver injury, whereas those receiving a similar cell population from WT B6 donors survived long term. Donor CD8 cells showed rapid activation, accelerated cell division, and reduced/delayed activation-induced cell death in allogeneic recipients in which donor cells were incapable of producing IFN-gamma. In consequence, the numbers of activated/effector (ie, CD25+, CD62L-, and CD44(high)) donor CD8 T cells in the recipients of GKO allo-HCT significantly exceeded those in mice receiving WT allo-HCT. These data show that IFN-gamma negatively regulates the CD8 T cell response by inhibiting cell division and promoting cell death and suggest that blockade of IFN-gamma could augment the severity of GVHD in patients undergoing allo-HCT.
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PMID:An essential role for IFN-gamma in regulation of alloreactive CD8 T cells following allogeneic hematopoietic cell transplantation. 1722 52

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic stem cell transplantation. Effector memory T cells (T(EM)) do not cause GVHD but engraft and mount immune responses, including graft-versus-tumor effects. One potential explanation for the inability of T(EM) to cause GVHD is that T(EM) lack CD62L and CCR7, which are instrumental in directing naive T cells (T(N)) to lymph nodes (LN) and Peyer patches (PP), putative sites of GVHD initiation. Thus T(EM) should be relatively excluded from LN and PP, possibly explaining their inability to cause GVHD. We tested this hypothesis using T cells deficient in CD62L or CCR7, transplant recipients lacking PNAd ligands for CD62L, and recipients without LN and PP or LN, PP, and spleen. Surprisingly, CD62L and CCR7 were not required for T(N)-mediated GVHD. Moreover, in multiple strain pairings, GVHD developed in recipients that lacked LN and PP. Mild GVHD could even be induced in mice lacking all major secondary lymphoid tissues (SLT). Conversely, enforced constitutive expression of CD62L on T(EM) did not endow them with the ability to cause GVHD. Taken together, these data argue against the hypothesis that T(EM) fail to induce GVHD because of inefficient trafficking to LN and PP.
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PMID:Effects of donor T-cell trafficking and priming site on graft-versus-host disease induction by naive and memory phenotype CD4 T cells. 1828 47

The study was aimed to analyze the difference of naive and memory CD4(+) and CD8(+) T-cell subsets between steady-state bone marrow (SS-BM) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) mobilized peripheral blood grafts (G-PB). Four CD4(+) and CD8(+) T-cell subsets classified according to the expression of CD45RA and CD62L were determined by three-color flow cytometry. The results showed that the percentage of CD4(+), CD8(+) T-cell subsets and the ratios of CD4/CD8 in G-PB were significantly higher than those in SS-BM (p < 0.05). The percentage of CD4(+) naive T-cells in G-PB was significantly lower than that in SS-BM (p < 0.001). As compared with SS-BM, the percentage of CD4(+) effector memory T-cells was significantly high in G-PB (p < 0.001). There were no significant differences in the percentages of the four CD8(+) T-cell subsets between SS-BM and G-PB (p > 0.05). The percentage of CD4(+)CD62L(+) T-cells in G-PB was significantly lower than that in SS-BM (p = 0.001). The absolute numbers of CD4(+) and CD8(+) T-cell subsets, the eight naive and memory CD4(+) and CD8(+) T-cell subsets were significantly higher in G-PB than those in SS-BM (p < 0.001). It is concluded that the difference of naive and memory CD4(+) and CD8(+) subsets between G-PB and SS-BM may partially explain why the incidence and severity of acute graft-versus-host disease (GVHD) was similar and the incidence of chronic GVHD was different after transplantation with SS-BM or G-PB.
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PMID:[Comparative analysis of naive and memory CD4(+) and CD8(+) T-cell subsets in rhG-CSF mobilized peripheral blood and steady-state bone marrow]. 1854 38

CD103 (alphaEbeta7) has been shown to be an excellent marker for identifying in vivo-activated FoxP3(+)CD4(+) regulatory T (Treg) cells. It is unknown whether reinfusion of in vivo-activated donor-type CD103(+) Treg cells from recipient can ameliorate ongoing chronic graft-versus-host disease (GVHD). Here, we showed that, in a chronic GVHD model of DBA/2 (H-2(d)) donor to BALB/c (H-2(d)) recipient, donor-type CD103(+) Treg cells from recipients were much more potent than CD25(hi) natural Treg cells from donors in reversing clinical signs of GVHD and tissue damage. Furthermore, in contrast to CD25(hi) natural Treg cells, CD103(+) Treg cells expressed high levels of CCR5 but low levels of CD62L and directly migrated to GVHD target tissues. In addition, the CD103(+) Treg cells strongly suppressed donor CD4(+) T-cell proliferation; they also induced apoptosis of in vivo-activated CD4(+) T and B cells and significantly reduced pathogenic T and B cells in GVHD target tissues. These results indicate that CD103(+) Treg cells from chronic GVHD recipients are functional, and reinfusion of the CD103(+) Treg cells can shift the balance between Treg cells and pathogenic T cells in chronic GVHD recipients and ameliorate ongoing disease.
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PMID:In vivo-activated CD103+CD4+ regulatory T cells ameliorate ongoing chronic graft-versus-host disease. 1924 67

Due to the potent immunoregulatory capacity, mesenchymal stem cells (MSCs) have been used in clinical trials to treat acute graft-versus-host disease (aGvHD), although the detailed in vivo mechanisms remain elusive. In a murine lethal aGvHD model, MSCs delayed the development of the disease. Interestingly, we found that MSC infusion increased the number of T lymphocytes in the secondary lymphoid organs (SLOs). Since the expression of CD62L and CCR7 is prerequisite for lymphocyte migration into SLOs, the in vitro experiments revealed that in the presence of MSCs, T lymphocytes (including CD4(+)CD25(+) regulatory T cells) preferred to take the naive-like phenotype (CD62L(+)/CCR7(+)) in mixed lymphocyte reaction and maintained the migratory activity elicited by secondary lymphoid tissue chemokine (SLC). Dendritic cells (DCs) are the initiator of immune response. CCR7 expression is pivotal for their maturation and migration into SLOs. However, CCR7 expression and SLC-driven migratory activity of DCs were remarkably suppressed by MSC coculture. The processes above were realized mainly through secretory mechanism. Consistently, MSC infusion maintained T lymphocytes to take CD62L(+)/CCR7(+) phenotype and decreased the CCR7 expression and proportion of DCs in SLOs of aGvHD mice. In conclusion, the altered migratory properties of T cells and DCs might contribute to the immunosuppressive activity of transplanted MSCs in the setting of aGvHD. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Mesenchymal stem cells alter migratory property of T and dendritic cells to delay the development of murine lethal acute graft-versus-host disease. 1863 70

The aim of this study was to investigate the ability of CD62L(-)/CD62L(+) T cells responding to antigens so as to explore the role of CD62L in GVHD. The T cells were stimulated by DCs-presenting specific antigen hCD4; the expression of CD62L on surface of T cells was detected by flow cytometry, the CD62(-) T/CD62L(+) T cells were gained by sorting selection method, then were stimulated with a new antigen (freeze-thaw antigen of EL4 cells), and the proliferation activity of CD62L(-) and CD62L(+) T cells was detected by flow cytometry after stimulating with different antigens at twice. The results showed that after stimulating with antigen, the expression level of CD62L(+) on surface of T cells was down-regulated from 60.34% to 36.75%, and the expression of CD62L(-) on surface of T cells increased from 30.04% to 63.15%. Compared with cells counts in area with high CFSE (M1), the average percentages of CD62L(+) T cells under stimulating with specific antigen (hCD4) on days 1 and 6 were (87.88 +/- 1.08)% and (86.88 +/- 1.46)% respectively (p > 0.05), and the average percentages of CD62L(+) T cells after stimulating with specific antigen on days 1 and 6 were (84.52 +/- 2.73)% and (84.21 +/- 2.33)% respectively (p > 0.05), there was no significant difference between two T cell groups on days 1 and 6. After stimulating with non-specific antigen, the average percentages of CD62L(+) T cells in MI area on days 1 and 6 were (76.49 +/- 2.41)% and (22.25 +/- 3.29)% respectively (p < 0.001), the average percentages of CD62l(-) T cells under conditions mentioned above were (77.35 +/- 3.82)% and (74.76 +/- 3.90)% respectively (p < 0.05). The results indicated that the proliferation activity of CD62L(+) T cells appeared, and the proliferation of CD62L(+) T cells did not occur. It is concluded that the CD62L(-) T/CD62l(+) T cells are gained in vitro, no proliferation reaction occurred in these two kinds of cells under stimulation of specific antigen, but the mitotic proliferation occur in CD62L(+) T cells under stimulation of nonspecific antigen, while no this reaction exists in CD62L(-) T cells under this condition. These results provide a new thinking to obtain the CD62L(-) T cells in vitro, to selectively eliminate the CD62L(+) T cells from graft and to decrease occurrence of GVHD in clinical practice.
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PMID:[Proliferative response of CD62L(-)/CD62L(+) T cells in mice to antigen stimulation]. 1923 72

Mouse studies demonstrated that infusion of CD4+CD25+ regulatory T cells (Tregs) prevented graft versus host disease (GVHD) lethality after bone marrow transplantation (BMT). But the potential impact of human Tregs on GVHD has not been well demonstrated. In this study, we demonstrated that human Tregs enriched from peripheral blood of healthy donors could be expanded ex vivo to clinically relevant cell numbers in 2-3 weeks while maintaining Foxp3, CD25, CTLA-4, and CD62L expression as well as in vitro suppressive function. Furthermore, injection of human PBL into NOD/SCID mice induced lethal xenogenic GVHD, but co-transfer of expanded human Tregs with human PBL significantly enhanced survival, reduced GVHD symptoms, and inhibited human IgG/IgM production in the NOD/SCID mice. These results demonstrated that ex vivo expanded human Tregs retained their in vivo suppressive activity and prevented lethal xenogeneic GVHD, revealing the therapeutic potential of expanded human Tregs for GVHD.
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PMID:Ex vivo expanded human CD4+CD25+Foxp3+ regulatory T cells prevent lethal xenogenic graft versus host disease (GVHD). 1941 Feb 43


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