Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD4(+)CD25(+) immunoregulatory T cells play a pivotal role in preventing organ-specific autoimmune diseases and in tolerance induction to allogeneic organ transplants. We investigated whether these cells could also control graft-versus-host disease (GVHD), the main complication after allogeneic hematopoietic stem cell transplantation (HSCT). Here, we show that the few CD4(+)CD25(+) T cells naturally present in the transplant regulate GVHD because their removal from the graft dramatically accelerates this disease. Furthermore, the addition of freshly isolated CD4(+)CD25(+) T cells at time of grafting significantly delays or even prevents GVHD. Ex vivo-expanded CD4(+)CD25(+) regulatory T cells obtained after stimulation by allogeneic recipient-type antigen-presenting cells can also modulate GVHD. Thus, CD4(+)CD25(+) regulatory T cells represent a new therapeutic tool for controlling GVHD in allogeneic HSCT. More generally, these results outline the tremendous potential of regulatory T cells as therapeutics.
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PMID:CD4(+)CD25(+) immunoregulatory T Cells: new therapeutics for graft-versus-host disease. 1216 68

In this case report we describe a novel treatment with two chimeric monoclonal antibodies (MoAb) targeting the autoimmune B cell clone responsible for bullous pemphigoid (BP) as a manifestation of steroid refractory chronic graft-versus-host disease (GVHD) that developed after unrelated cord blood transplantation. Monitoring the BP-specific circulating antibodies and CD25-expressing activated T lymphocyte subset led us to combine anti-CD20 (Rituximab) mediated B cell ablation with anti-CD25 (Daclizumab) therapy to block CD4(+) T cell help. Complete clinical and serologic response was achieved within 4 weeks of initiation of therapy allowing global immunosuppression to be dramatically reduced.
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PMID:Combination treatment of bullous pemphigoid with anti-CD20 and anti-CD25 antibodies in a patient with chronic graft-versus-host disease. 1564 Aug 17

Preconditioning with the nonmyeloablative regimen total lymphoid irradiation (TLI) before hematopoietic cell transplantation facilitates the establishment of mixed chimerism and protects against graft-versus-host disease. We reported that the development of mixed chimerism requires interleukin (IL)-4 and is associated with increased host anti-donor TH2 cells, but the effect of TLI on the differentiation of immunocompetent donor cells has not been investigated. To examine the extent to which TLI preconditioning influences donor T cells, we measured responses of transgenic CD4+cells specific for ovalbumin peptide (OVA-Tg) following in vivo and in vitro antigen stimulation in a TLI-preconditioned environment. OVA-Tg cells that were adoptively transferred into TLI-preconditioned mice that express cross-reactive antigens produced more IL-4 and less interferon-gamma and IL-2 than controls when stimulated with OVA peptide one week later. OVA-Tg primed in vitro with spleen from TLI-preconditioned mice generated more TH2 and fewer TH1 cells when stimulated in recall enzyme-linked immunosorbent spot (ELISPOT) assays with OVA peptide. Naive OVA-Tg up-regulated CD69 and CD25 normally following stimulation with OVA peptide in the presence of spleen from TLI-preconditioned mice, but proliferated less and secreted less IL-2 than controls. Surprisingly, naive OVA-Tg secreted IL-4 in primary cultures that were stimulated with OVA peptide in the presence of spleen from TLI-preconditioned mice. This response depends on CD4+cells from TLI-spleen, which constitutively produce IL-4 and are composed primarily of CD4+-natural killer T (TNK) cells. Thus, TLI preconditioning enriches for IL-4-secreting and TNK-like CD4+cells that may function in the protection from graft-versus-host disease by redirecting the differentiation of immunocompetent donor CD4+cells toward TH2 and away from pathogenic TH1 cells.
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PMID:Total lymphoid irradiation nonmyeloablative preconditioning enriches for IL-4-producing CD4+-TNK cells and skews differentiation of immunocompetent donor CD4+ cells. 1240 8

OPi (formerly Orphan Pharma International) is developing inolimomab, an anti-interleukin-2 receptor (CD25) monoclonal antibody for the potential treatment of acute graft versus host disease. As of April 2001, inolimomab was undergoing phase II/III clinical trials.
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PMID:Inolimomab (OPi). 1243 Oct 19

We have previously identified donor-derived Thy1+ alphabeta T-cell receptor (TCR)+ CD4+ CD8- regulatory T-cells that suppress GVH reactivity induced by donor leukocyte infusion (DLI) after BMT. These cells develop in the recipient thymus and may play a role in the maintenance of donor-host tolerance after allogeneic BMT. In the present study, we sought to further characterize the T-cells responsible for the regulatory cell activity in our model. Lethally irradiated recipient AKR mice (H-2k) received transplants of BM from CD25-deficient (-/-) C57BL/6 mice (H-2b). Recipients of CD25-deficient BM developed more severe GVHD after DLI than did recipients of normal BM, a result that indirectly suggests that CD4+ CD25+ regulatory T-cells are important to the suppression of GVH reactivity after allogeneic BMT. GVHD was accompanied by mortality, body weight loss, and elevated percentages of T-cells from the DLI in the peripheral blood in mice that received CD25-deficient BM compared to mice that received normal BM. Both CD40-CD40L and CD28-B7 costimulatory pathways have been implicated in the generation of CD25+ regulatory T-cells. Therefore, we tested whether deficiency in either of these pathways affected the activity of donor BM-derived regulatory T-cells. The absence of CD40L did not affect the regulatory T-cells (ie, recipient mice were still protected from DLI-induced GVHD). In contrast, use of marrow from CD28-deficient mice resulted in complete loss of suppression of GVH reactivity. Thus, CD28 but not CD40L was critical for the generation and/or activation of immunoregulatory T-cells that suppressed GVHD induced by DLI. Together, the results of these experiments suggest that CD4+ CD25+ regulatory T-cells suppress GVH reactivity after BMT and that CD28 expression is indispensable for the generation of these cells.
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PMID:CD25+ immunoregulatory T-cells of donor origin suppress alloreactivity after BMT. 1243 47

To explore the feasibility of using CD25 monoclonal antibody (Basiliximab) in T-cell undepleted allo-BMT with graft from haplotype-matched related donor for acute GVHD prophylaxis. Twenty-eight patients with leukemia received allo-BMT from HLA two or three loci mismatched related donors. The donors were given G-CSF (Lenograstim) 250 micro g/d for 7 doses prior to marrow harvest. CSA, MTX, ATG and mycophenolate mofetil (MMF) were combined for GVHD prophylaxis. ATG 5 mg/(kg.d) was infused from day 4 to day 1 before transplantation and MMF was administered from day 7. In the study group, the patients received additional CD25 monoclonal antibody for aGVHD prophylaxis. CD25 20 mg each by 30 min intravenous infusion on 2 hours before transplantation and day 4 after transplantation was administered while no application of CD25 in the controls. The outcomes of transplantation were compared between the stud y and control groups. The results showed that the median number of CD34(+) cell in graft was 5.9 x 10(6)/kg in the control group and 7.9 x 10(6)/kg in the study group. The median number of CD3(+) cell was 48 x 10(6)/kg and 52 x 10(6)/kg respectively (P > 0.05). All patients showed 100% donor-typed hematopoietic cells after transplantation by cytogenetic evidence. Five out of fifteen patients in the control group experienced II - IV acute GVHD. While none of thirteen in the study group developed the II - IV acute GVHD. However, none in both groups developed extensive cGVHD. The median follow-up duration was 8 (3-15) months in the study group and 26 (15-36) months in control. In the study group, one patient died from transplant related mortality (CMV infection); no one relapsed; and 12/13 patients survived in disease-free situation within the period of follow-up. In the control group, six patients died from transplant related mortality (3 GVHD, 2 infection and 1 relapsed) and 9/15 patients survived in disease-free situation. The one-year probabilities of disease-free survival (DFS) in two groups were significantly different (P < 0.05). It is concluded that the transplant from haploidentical donors used CD25 antibody is effective and feasible in preventing acute severe GVHD and improving DFS. The major histocompatibility barrier in the haploidentical related allo-BMT could be crossed by donors primed with G-CSF and GVHD prophylaxis with CD25 antibody in the hosts.
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PMID:[A clinical study of haploidentical and G-CSF primed bone marrow transplantation by using CD25 for aGVHD prophylaxis]. 1251 46

To investigate the mechanisms underlying the issue that bone marrow mesenchymal stem cells (MSC) could trigger low responsiveness of allogeneic T lymphocytes against alloantigens, phenotypes of T cells were analysed with flow cytometry before and after coculture of allogeneic T lymphocytes with MSC. Further, expression of cytokines including IL-4, IFN-gamma and TGF-beta1 was evaluated by RT-PCR and ELISA as well. The results showed that CD8(+) subpopulation was increased and CD25(+) subset was decreased in proportion after coculture of allogeneic T lymphocytes with MSC for 2 weeks. RT-PCR assay showed that MSC expressed TGF-beta1 but not IL-4 and IFN-gamma, and the result was further proved by ELISA assay showing that the secretion of TGF-beta1 reached to 1 ng/ml in 72 hours. It was concluded that allogeneic MSC suppressed T cells activation by alteration of T cell subpopulations. The suppressive effect was at least in part due to the secretion of TGF-beta1. The results indicate that MSC pretreatment might be useful in the prevention of GVHD in HLA-mismatched bone marrow transplantation and further donors for hematopoietic stem cells could be selected from greater potentials.
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PMID:[Mesenchymal stem cells suppress allogeneic T cell responses by secretion of TGF-beta1]. 1251 58

Although graft-versus-host (GVH) disease (GVHD) is usually associated with graft versus leukemia (GVL), GVL can occur in the absence of clinical GVHD. There is evidence to suggest that GVL and GVH are mediated by different clones of T cells. The objective of this study was to identify the two types of T cells based on their receptor sequences. To this end we used irradiated nonleukemic cells from recipients as stimulator cells in a primary mixed leukocyte reaction (MLR). The activated CD4(+) donor T cells that expressed CD25 were purified by cell sorting. To prepare GVL-specific T cells, alloreactive T cells in the primary MLR were first depleted with an anti-CD25 immunotoxin. The remaining T cells had negligible alloreactivity in a secondary MLR. The allodepleted cells were then stimulated by using purified leukemia cells from the same individual as stimulator cells, and the CD25(+)-activated cells were purified by cell sorting. The GVL- and GVH-specific T cells were analyzed for their T cell receptor (TCR) clonality by using anchored RT-PCR of all the TCRbeta locus complementarity-determining region 3 (CDR3) sequences. By comparing TCRbeta CDR3 sequences from transformed bacterial colonies, we were able to demonstrate that T cells mediating GVH were different from those mediating GVL in each of the eight HLA-mismatched and one HLA-matched donor/recipient pairs. By using the appropriate TCRbeta CDR3-specific primers and probes, the GVH- and GVL-specific clones were monitored in a recipient undergoing an allogeneic stem cell transplant from her HLA-matched related donor.
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PMID:Definitive separation of graft-versus-leukemia- and graft-versus-host-specific CD4+ T cells by virtue of their receptor beta loci sequences. 1253 22

To analyze the relation of early immune reconstitution with acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (all-HSCT), the changes of CD3(+), CD4(+), CD8(+), CD25(+) and CD69(+) cells in peripheral blood from 26 patients with hematologic malignancies were assayed by flow cytometry within 2 months after allo-HSCT. All patients achieved hematopoietic reconstitution, and grade I and II - IV GVHD were developed in 9 and 5 patients, respectively. CD25(+) cells were increased in patients aGVHD at week 2 after transplantation and the peak value was appeared at week 3. The increase of CD25(+) cells was preceded the occurence of clinical signs of aGVHD. The maximal levels of CD25(+) cells increase correlated significantly with the severity of aGVHD. The increase of CD25(+) cells was declined along with remission of aGVHD signs. Our results suggest that analyzing immune reconstitution after allo-HSCT could predict occurence of aGVHD, and CD25(+) cell increase prior occurence of aGVHD is predictive marker for aGVHD.
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PMID:[Study on Relation of Early Immune Reconstitution with Acute Graft-Versus-Host Disease] 1257 78

We previously reported that interleukin-10 (IL-10) and transforming growth factor (TGF)-beta treatment of primary mixed lymphocyte reaction (MLR) cultures resulted in secondary alloantigen-specific hyporesponsiveness and protection from graft-versus-host disease (GVHD) lethality. Here, we report that CD4+ T cells recovered from the IL-10- and TGF-beta-treated primary MLR cultures have immunoregulatory function. Tolerized cells significantly inhibited proliferation of naive alloreactive CD4+ T cells in a primary MLR. Inhibition of the naive alloresponse was observed with as few as 1 tolerized cell to 10 naive responder cells. Tolerized cells were able to significantly reduce GVHD lethality when injected with naive alloreactive CD4+ T cells into major histocombatibility class (MHC) II disparate recipients. Rigorous CD25 depletion of the primary MLR had no effect on generation of a regulatory capacity, suggesting that the regulatory cells likely originated from CD4+CD25- T cells. Immune suppression was mediated independently of IL-10 and TGF-beta production, as neutralizing antibodies for IL-10, IL-10R, and TGF-beta were unable to revert suppression, and IL-10- deficient CD4+ T cells were able to mediate in vitro and in vivo suppression. The generation of immunoregulatory cells from a CD4+CD25- population during tolerization with IL-10 and TGF-beta provides an additional mechanism to prevent GVHD lethality by T cells that may escape full tolerance induction.
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PMID:IL-10 and TGF-beta induce alloreactive CD4+CD25- T cells to acquire regulatory cell function. 1260 34


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