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 review summarizes recent results investigating the role of certain cytokine gene polymorphisms, including those of TNF-alpha, IFN-gamma, IL-6, IL-10 and IL-1 receptor antagonist (IL-1Ra), in allogeneic stem cell transplantation. It discusses their role in predicting outcome and the development of a genetic risk index for graft versus host disease (GvHD) in HLA-matched sibling transplants. By the comparative use of an in vitro human skin explant model, initial results suggest that certain cytokine gene polymorphisms may be associated with more severe disease.
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PMID:Predicting outcome in hematological stem cell transplantation. 1254 63

A coordinated effort combining bioinformatic tools with high-throughput cell-based screening assays was implemented to identify novel factors involved in T-cell biology. We generated a unique library of cDNAs encoding predicted secreted and transmembrane domain-containing proteins generated by analyzing the Human Genome Sciences cDNA database with a combination of two algorithms that predict signal peptides. Supernatants from mammalian cells transiently transfected with this library were incubated with primary T cells and T-cell lines in several high-throughput assays. Here we describe the discovery of a T cell factor, TIP (T cell immunomodulatory protein), which does not show any homology to proteins with known function. Treatment of primary human and murine T cells with TIP in vitro resulted in the secretion of IFN-gamma, TNF-alpha, and IL-10, whereas in vivo TIP had a protective effect in a mouse acute graft-versus-host disease (GVHD) model. Therefore, combining functional genomics with high-throughput cell-based screening is a valuable and efficient approach to identifying immunomodulatory activities for novel proteins.
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PMID:TIP, a T-cell factor identified using high-throughput screening increases survival in a graft-versus-host disease model. 1283 85

We have evaluated recovery of CD56 positive and other cell types following allogeneic stem cell transplantation and have found that the recovery of CD56 positive cells was faster than other lymphoid cells after allogeneic stem cell transplantation, while the recovery of CD4 positive cells was markedly delayed. Chimerism analysis showed that mixed chimerism was often observed in younger (<30 years old) patients. Mixed chimerism in older (> or =30 years old) patients was associated with rejection and relapse, while this was not found in younger patients. Among the chimerism of various cell populations, donor-derived CD56-positive cells are important in early engraftment when determined in allogeneic nonmyeloablative stem cell transplantation (allo-NST), regardless of the proportion of donor-derived CD3-positive cells. Complementarity-determining region three (CDR3) size spectratyping in T-cell receptor (TCR) chain subfamilies (Vbeta) showed that high level of diversity in TCR Vbeta repertoire is important for a late rejection and skewed TCR Vbeta repertoire is correlated with the occurrence of graft-versus-host disease (GVHD) especially chronic GVHD. Expression of inhibitory natural killer (NK) cell receptors such as CD158b and CD94/NKG2A on peripheral CD3-negative and -positive cells were increased in parallel with GVHD. Interestingly, these cells appeared to control GVHD, while preserving graft-versus-leukemia (GVL) effect. Analysis of cytokine gene expression in peripheral blood mononuclear cells showed that type 1 helper T cells (Th1)-derived cytokines increased in severe GVHD, while Th2-derived cytokines such as IL-4, IL-10 and IL-13 increased in mild GVHD. These results indicate that Th2 cells suppress GVHD, although Th1 cells augment GVHD. Taken together, evaluation of immune reconstitution and tolerance in patients receiving allogeneic stem cell transplantation from the various viewpoints is essential and useful to obtain better clinical outcome.
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PMID:Immune reconstitution and tolerance after allogeneic hematopoietic stem cell transplantation. 1262 23

Adoptive T-cell therapy using CD3/CD28 co-stimulation likely requires in vivo generation of antigen specificity. Because CD28 promotes TH1/TC1 (T1) or TH2/TC2 (T2) differentiation, costimulation may generate donor T1 or T2 cells capable of differentially mediating allogeneic graft-versus-tumor (GVT) effects and graft-versus-host disease (GVHD). Costimulation under T1 or T2 conditions indeed generated murine TH1/TC1 cells secreting interleukin-2/interferon-gamma (IL-2/IFN-gamma) or TH2/TC2 cells secreting IL-4/IL-5/IL-10. In vivo, allogeneic T1 cells expanded, maintained T1 secretion, and acquired allospecificity involving IFN-gamma and IL-5. In contrast, allogeneic T2 cells expanded less and maintained T2 secretion but did not develop significant allospecificity.Allogeneic, but not syngeneic, T1 cells mediated a GVT effect against host-type breast cancer cells, as median survival time (MST) increased from 25.6 +/- 2.6 (tumor controls) to 69.2 +/- 5.9 days (P < 1.2 x 10(-9)). This T1-associated GVT effect operated independently of fasL because T1 cells from gld mice mediated tumor-free survival. In contrast, allogeneic T2 cells mediated a modest, noncurative GVT effect (MST, 29 +/- 1.3 days; P <.0019). T1 recipients had moderate GVHD (histologic score, 4 of 12) that contributed to lethality after bone marrow transplantation; in contrast, T2 recipients had minimal GVHD (histologic score, 1 of 12). CD3/CD28 co-stimulation, therefore, generates T1 or T2 populations with differential in vivo capacity for expansion to alloantigen, resulting in differential GVT effects and GVHD.
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PMID:CD3/CD28-costimulated T1 and T2 subsets: differential in vivo allosensitization generates distinct GVT and GVHD effects. 1285 80

To evaluate the development of the neonatal immune system, we measured T lymphocyte response to Con A, intracellular IL-2, IL-4, IFN-gamma and IL-10 production, and natural killer cell (NKC) activity in 12 very preterm, 12 preterm and 20 term neonates, 10 children and 10 adults. Immunoproliferation to Con A was significantly lower in cord blood than in children or adults. The percentage of CD4+ lymphocytes was significantly higher in newborns while CD8+ cells were higher at older ages, with a resulting gradual decline of the CD4+/CD8+ ratio. The percentage of IL-2-producing CD4+ and CD8+ cells was higher in all newborn groups than in children and adults, while the percentage of IL-4-producing cells was higher for CD8+ and lower for CD4+ cells in cord blood than in children and adults. Neonates had substantially lower percentages of CD4+ and CD8+ IFN-gamma-producing cells. A significant negative correlation was observed between gestational age and IFN-gamma-CD4+-, IL-2-CD8+-, and IL-10- CD4+-producing cells. In addition, a positive correlation was found between gestational age and IL-10-CD8+-producing cells. Percentages of CD4+/CD45RA+ cells were higher and CD4+/CD45RO+ percentages were lower in newborns than in children and adults. NKC activity in infants was significantly correlated with gestational age and significantly impaired compared to children and adults. On the whole, these results suggest a gradual development of immunity during gestation and show significant immaturity of cellular immune response at birth. The reduction of NKC activity, the lower proliferative response of T cells, the reduced cytotoxic response and a dysregulated cytokine production may contribute to the neonatal increased risk of infection and to the low incidence of graft-versus-host disease after cord blood transplantation.
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PMID:Age-related changes in intracellular TH1/TH2 cytokine production, immunoproliferative T lymphocyte response and natural killer cell activity in newborns, children and adults. 1459 40

In order to apply for reducing graft versus host disease in allogeneic stem cell transplantation, the study concerning the induction of specific T cell anergy was designed. Normal allogeneic lymphocytes, which were co-cultured with IL-10-treated immature dendritic cells in the first mixed leukocyte culture (MLC), were cultured with mature dendritic cells of the same origin as IL-10-treated immature dendritic cells in the second MLC. By co-culturing with IL-10-treated immature dendritic cells, the response of normal lymphocytes to mature dendritic cells cultured from the same individual as that of IL-10-treated dendritic cells was markedly reduced, compared with the lymphocytes cultured with non-treated dendritic cells or IL-10-treated dendritic cells from a third party individual. The present study demonstrated that antigen specific T cell anergy was generated by priming allogeneic lymphocytes with IL-10-treated immature dendritic cells. These data suggested the applicability of IL-10-treated recipient dendritic cells for the induction of recipient cell-specific donor T cell anergy in donor graft.
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PMID:Induction of T cell anergy by the treatment with IL-10-treated dendritic cells. 1469 Jul 19

Graft versus host disease is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Galectin-1, a mammalian lectin that modulates T cell function and apoptosis, has been shown to be immunomodulatory in animal models of autoimmune disease. We investigated the efficacy of galectin-1 in a murine model of graft versus host disease and found that 68% of galectin-1-treated mice survived, compared to 3% of vehicle-treated mice. Galectin-1-treated animals also had reduced inflammatory infiltrates in tissues compared to animals treated with vehicle alone. Galectin-1 did not affect engraftment of donor hematopoietic cells. However, galectin-1-treated animals demonstrated increased cellularity in bone marrow and spleen with increased numbers of splenic B cells and CD4 T cells compared to those animals treated with vehicle alone. Galectin-1 treatment also significantly improved reconstitution of normal splenic architecture following transplant. Production of type I cytokines interleukin-2 (IL-2) and interferon-gamma was reduced in splenocytes derived from galectin-1-treated transplanted mice when compared to animals treated with vehicle alone, while production of the type II cytokines, IL-4 and IL-10, was similar between the two groups of animals. Although splenocytes from galectin-1-treated transplanted animals responded to both third party antigens and leukemic challenge, host alloreactivity was significantly reduced when compared to cells from vehicle-treated animals. These results demonstrate that galectin-1 therapy is capable of increasing survival and suppressing the graft versus host immune response without compromising engraftment or immune reconstitution following allogeneic hematopoietic stem cell transplant.
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PMID:Amelioration of graft versus host disease by galectin-1. 1469 44

Ultraviolet (UV) light is known to induce skin cancers by causing DNA gene mutations and inducing immunosuppression. Taking advantage of these immunosuppressive capacities, UV light has been used, with different modalities, as an immunosuppressive therapy in a variety of diseases including allograft rejection and graft-versus-host disease. Phototherapy includes UVB irradiation, UVA irradiation, oral psoralen (+)UVA irradiation (PUVA), photodynamic therapy, and extracorporeal photopheresis, which consists of infusion of UVA-irradiated autologous leukocytes collected by apheresis and incubated with 8-methoxypsoralen. According to numerous experimental models and human data, there is increasing evidence that UVB irradiation and extracorporeal photopheresis can induce regulatory T cells and anticlonotypic activity. These therapies induce apoptosis of activated T cells or of extracorporally treated mononuclear cells, and up-regulate the expression of costimulary molecules and adhesion molecules on antigen presenting cells. UVB- or UVA-induced apoptotic cells could secrete immune suppressive cytokines (interleukin (IL)-4, IL-10). The processing and presentation of apoptotic T cell antigens from clones of pathogenic T cells by activated antigen presenting cells might explain the induction of systemic anticlonotypic activity by photopheresis. This induction of cell-mediated suppressive activity opens up future prospects with the aim of expanding regulatory T cells and/or anticlonotypic activity, especially by photopheresis in organ and cell transplantation.
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PMID:Ultraviolet light-induced regulatory (suppressor) T cells: an approach for promoting induction of operational allograft tolerance? 1472 67

Because a relatively low incidence and severity of graft-versus-host disease after umbilical cord blood (UCB) transplantation is observed, we investigated whether T cells from UCB or adult blood (AB) were differentially activated by antigen-presenting cells with or without human leukocyte antigen (HLA)-DR expression. T cells from UCB or AB, or CD45RA(+) naive T cells and CD45RO(+) memory T cells separated from AB, were stimulated with the HLA-DR(+) or HLA-DR(-) cell line AML193. On days 1-3 after stimulation, numbers of interleukin (IL)-2, IL-4, IL-10 or interferon gamma (IFN-gamma)-secreting cells were determined by enzyme-linked immunospot analysis. No IL-4 or IL-10 was produced. AML193-DR(+) cells induced IL-2 and IFN-gamma secretion with slower kinetics and lower levels in UCB T cells than in AB T cells. AML193-DR(+) cells induced comparable IL-2 but higher IFN-gamma secretion in CD45RA(+) T cells from AB than in UCB T cells. AML193-DR(-) cells did not induce IL-2- or IFN-gamma secretion in UCB T cells, but stimulated both CD45RA(+) and CD45RO(+) T cells from AB to secrete IL-2 and IFN-gamma. Thus, not only the absence of memory T cells but also the inability to respond to HLA-DR-negative antigen-presenting cells and the slower kinetics and level of activation found for naive T cells from UCB as compared with AB may partly explain the reduced antirecipient reactivity after UCB transplantation.
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PMID:Umbilical cord blood-naive T cells but not adult blood-naive T cells require HLA class II on antigen-presenting cells for allo-immune activation. 1512 Jan 87

Mycophenolate mofetil (MMF) is a newly developed immunosuppressor, widely used in allogeneic bone marrow transplant. The purpose of this study was to evaluate the effects of mycophenolic acid (MPA), the active metabolite of MMF in vivo, on the maturation and immunologic function of murine bone marrow-derived dendritic cells (DC), and to explore the underlying mechanisms of MMF in graft versus host disease. Cultured DC were treated with MPA at doses of 0.01 and 0.1 micro mol/L. The immunophenotype of DC in control and treated groups was analyzed by flow cytometry. The capability of antigen presentation and the stimulatory activity of the DC on allogeneic T cells were tested by incorporation of (3)H-TdR and mixed lymphocyte reaction respectively. IL-12 production in culture supernatant and the levels of Th1/Th2 cytokines such as IL-2, IFN-gamma, IL-4 and IL-10 in mixed lymphocyte reaction (MLR) supernatant were examined by ELISA assay. The results showed that DCs cultured in the presence of MPA expressed low levels of CD40, CD80 and CD86, and exhibited weak activity in stimulating the proliferation of allogeneic T cells and antigen presenting function with a concurrent reduction of IL-12 production. Allogeneic T cells stimulated by MPA-treated DC expressed higher levels of Th2 cytokines such as IL-4 and IL-10 but lower levels of Th1 cytokines such as IL-2 and IFN-gamma than those stimulated by DC without MPA treatment. It is concluded that MPA, and hence MMF, exerts a negative effect on the maturation and immunologic functions of DC in culture, and drives a shift of Th1 to Th2 cytokines in MLR.
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PMID:[The effects of mycophenolic acid on the maturation and immunologic function of murine bone marrow-derived dendritic cells]. 1515 35


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