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)

The 4-aminoquinolines, chloroquine and hydroxychloroquine, are established, with a 52% response rate, as therapy for human steroid-refractory GVHD after BMT. Chloroquine affects numerous mechanisms that play a role in GVHD, including inhibition of major histocompatibility complex (MHC) class II antigen presentation, cytokine production, and antigen-presenting cell activation by bacterially derived CpG oligodeoxynucleotides (ODNs). Using an MHC-disparate murine model, we evaluated the effect of chloroquine treatment on the development of acute GVHD. We assessed the effect of chloroquine on the immunostimulatory responses induced by CpG ODNs after BMT. We also evaluated the impact of chloroquine on cytokine-producing populations known to affect GVHD, including CD4+ and CD8+ T-cell and CD3(+)/NK1.1(+) natural killer T-cell (NKT cell) populations. Twelve (86%) of 14 mice receiving phosphate-buffered saline solution (PBS) developed lethal GVHD; only 4 (29%) of 14 mice receiving chloroquine 20 mg/kg 3 times per week developed lethal GVHD (P < .01). Chloroquine significantly suppressed CpG ODN-induced splenic proliferation and interleukin 6 (IL-6) production associated with GVHD. Chloroquine suppressed CD8+ T-cell production of IL-2 and IL-4 associated with GVHD in this model and maintained an early expansion (day 7) of splenic NKT cells. These results indicate that the 4-aminoquinolines are effective in therapy for or prevention of acute GVHD secondary to MHC disparities. Chloroquine actions may include inhibition of CpG ODN augmentation of GVHD. Other mechanisms involved may include suppression of CD8+ T-cell production of IL-2 and IL-4 and an increase in NKT cells associated with GVHD inhibition by chloroquine.
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PMID:Chloroquine prevention of murine MHC-disparate acute graft-versus-host disease correlates with inhibition of splenic response to CpG oligodeoxynucleotides and alterations in T-cell cytokine production. 1252 76

Graft-versus-host disease (GvHD) mediated by donor T cells recognizing host alloantigens is associated with beneficial graft-versus-tumor effects in recipients of allogeneic hematopoietic cell transplants. Since leukemias and lymphomas reside largely within the lymphohematopoietic system, we have proposed that the desired graft-versus-leukemia or graft-versus-lymphoma effect can be separated from the complication of GvHD by confinement of the graft-versus-host alloresponse to the lymphohematopoietic tissues. Since the new sphingosine-1-phosphate receptor agonist immunosuppressive drug FTY720 leads to trapping of T cells in secondary lymphoid tissues, we evaluated the possibility that this drug could diminish GvHD, a disease involving epithelial target tissues, while permitting a beneficial alloresponse to take place within the lymphohematopoietic system, leading to graft-versus-lymphoma effects. We demonstrate here that FTY720 markedly reduces GvHD in a clinically relevant, haploidentical strain combination, while permitting antitumor effects against a T cell lymphoma of unshared host MHC haplotype to proceed unhindered. These results establish a potential new immunotherapeutic approach to separating graft-versus-leukemia effects from GvHD.
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PMID:Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720. 1261 20

Graft-versus-host disease (GVHD) is a severe disorder and despite therapeutic efforts to decrease its distressing clinical manifestations, treatment is still not optimal. Here we report the results of studies, in which the purine analogue, fludarabine phosphate, was used in an attempt to modify and decrease GVHD after stem cell transplantation, across major histocompatibility barriers for murine leukemia. B-cell leukemia (BCL-1) bearing (BALB/c x C57BL/6) F1 mice received two cycles of fludarabine (0.8 mg/kg) for 5 days every 2 weeks, followed by 400 mg/kg cyclophosphamide i.p. Animals were then transplanted with C57BL/6 precursor cells and the development of leukemia and extent of GVHD was monitored both clinically and histopathologically. In the fludarabine-treated group, only nine of 28 (32%) mice developed leukemia, compared to 25 of 33 (76%) of control animals (P=0.0006 ). Mice treated with fludarabine-containing regimens prior to transplantation also had much less GVHD both clinically and at autopsy, while graft-versus-leukemia appeared to be augmented in the same animals.
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PMID:Fludarabine in combination with cyclophosphamide decreases incidence of GVHD and maintains effective graft-versus-leukemia effect after allogeneic stem cell transplantation in murine lymphocytic leukemia. 1262 1

Patients with graft-versus-host disease (cGVHD) suffer from oral dryness and increased levels of oral infections and mucosal pathologies. The purpose of the current study was dual: 1) to investigate the salivary functional (sialometry) and compositional (sialochemistry) alterations induced by the disease during a 12-month period following the onset of the disease; and 2) to evaluate the effect of Salagen 30 mg/d on the salivary biochemical and immunological composition in cGVHD patients. Significant higher concentrations of salivary sodium (Na), magnesium (Mg), total protein (TP), albumin (Alb), epidermal growth factor (EGF), and total IgG accompanied by a concomitant increase in total IgA that did not reach significant value was observed in cGVHD patients in comparison with controls at both resting and stimulated conditions (p < 0.05) while salivary levels of potassium (K), calcium (Ca), and phosphate (P) were not altered. Two weeks of oral Salagen 30 mg/d resulted in normalization of the salivary biochemical and immunological compositional alterations in the cGVHD patients. Oral pilocarpine was able to reduce and normalize the elevated levels of Na, Mg, TP, Alb, EGF, IgG, and IgA salivary concentrations at both resting and stimulated conditions. The ability of oral pilocarpine to normalize and reverse salivary biochemical and immunological alterations induced by cGVHD is parallel to its stimulatory effect on salivary flow rates, as we previously showed. As the biochemical and immunological composition of the saliva results in its antimicrobial protective characteristics, the ability of oral pilocarpine (Salagen) to abrogate cGVHD salivary gland abnormalities may be of clinical importance.
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PMID:Sialometrical and sialochemical analysis of patients with chronic graft-versus-host disease--a prolonged study. 1264 7

Impaired T-cell immune reconstitution is a major complication after allogeneic bone marrow transplantation (BMT) and is particularly exacerbated in the setting of graft-versus-host disease (GVHD). Conventional approaches to reduce GVHD, such as T-cell depletion or pharmacologic immunosuppression, typically fail to enhance T-cell immunity and often further exacerbate this problem. An alternative strategy to mitigate GVHD severity is the selective elimination of graft-versus-host-reactive donor T cells by using an incorporated thymidine kinase suicide gene. This approach has been shown to effectively reduce GVHD, although the effect of this strategy on T-cell reconstitution is unresolved. We addressed this question in a murine BMT model (C57BL/6 [H-2(b)] --> AKR/J [H-2(k)]) in which donor and recipient differ at major and minor histocompatibility antigens. Lethally irradiated AKR recipients transplanted with T cell-depleted bone marrow plus thymidine kinase-positive T cells followed by post-BMT ganciclovir (GCV) administration had more prompt and complete normalization of the T-cell repertoire than phosphate-buffered saline-treated GVHD control animals. By 60 days after transplantation, mice administered GCV had T-cell repertoires that were virtually indistinguishable from those of mice that underwent transplantation with T cell-depleted bone marrow alone (no GVHD controls) when assayed by T-cell receptor (TCR) spectratyping. In contrast, phosphate-buffered saline-treated animals had persistent skewing in most Vbeta families. T cells obtained from GCV-treated mice also had significantly higher in vitro proliferative responses after posttransplantation inoculation with ovalbumin than GVHD animals, indicating that CD4(+) T-cell responses against a nominal antigen were better preserved in these chimeras. Finally, GCV-treated mice had augmented immune reconstitution in response to exogenous interleukin-7 administration, as evidenced by increased overall spleen cellularity and absolute numbers of T and B cells. This was in contrast to GVHD control animals, which had a blunted response to interleukin-7 administration. These data indicate that GVHD severity can be significantly reduced by selective elimination of alloreactive donor T cells without compromise of T-cell immunity. Moreover, in light of previous studies demonstrating that this strategy can reduce GVHD without loss of alloengraftment and antileukemia reactivity, further examination of this approach in humans seems warranted.
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PMID:Selective elimination of alloreactive donor T cells attenuates graft-versus-host disease and enhances T-cell reconstitution. 1467 13

Allogeneic stem cell transplantations (SCT) are currently being used as a therapy for hematological malignancies, some solid tumors and nonmalignant bone marrow deficiencies. Nevertheless, clinical applicability is limited due to toxicity of conditioning regimens, graft-versus-host disease (GVHD) and the scarcity of HLA-identical family donors. New concepts are based on nonmyeloablative conditioning to reduce toxicity, prevention or amelioration of GVHD and the use of haploidentical donors to increase donor availability. To combine these requirements, we have developed a nonmyeloablative conditioning regimen, consisting of low-dose total body irradiation and cyclophosphamide-based chemotherapy. In a haploidentical F1 --> F1 mouse model, this nonmyeloablative transplantation protocol resulted in stable full donor chimerism, but also in the development of severe GVHD. Administration of keratinocyte growth factor (KGF) reduced GVHD, evident as reduced weight loss and a lesser degree of dermatitis, compared to saline-treated controls. KGF preserved plasma citrulline and tumor necrosis factor-alpha levels, both indicative for reduced injury to the gastrointestinal tract. This was confirmed by histological findings. At 6 months after transplantation, survival rates were significantly higher in KGF-treated animals as compared to phosphate buffered saline-treated controls. These results indicate that KGF preserves gut integrity and might therefore contribute substantially to reduction of lethal GVHD in (nonmyeloablative) haploidentical transplantation.
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PMID:Keratinocyte growth factor ameliorates acute graft-versus-host disease in a novel nonmyeloablative haploidentical transplantation model. 1615 17

A 60-year-old Japanese man with myelodysplastic syndrome (MDS) and effort angina was referred to our clinic for treatment of MDS. The patient was transfusion-dependent and displayed coronary artery disease (CAD) with 99% obstruction of the left anterior descending coronary artery. Treatment comprised reduced-intensity hematopoietic stem cell transplantation with administration of fludarabine phosphate (180 mg/m(2)) and busulfan (8 mg/kg), followed by allogeneic peripheral blood stem cell transplantation from an HLA-matched sister. The regimen was well tolerated, and engraftment occurred rapidly without any therapy-related complications, including cardiovascular attack. Sex chromosome analysis by fluorescence in situ hybridization revealed complete donor chimerism on day 29 for bone marrow cells and on day 59 for peripheral blood leukocytes. The patient became transfusion-independent on posttransplantation day 8. As of 22 months postoperatively, he remains well, with 100% Karnofsky performance status, a limited type of chronic graft-versus-host disease, and no recurrence of disease. The clinical course of the patient suggests that this preparative regimen allows safe allogeneic stem cell transplantation for MDS patients with severe CAD.
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PMID:Successful reduced-intensity hematopoietic stem cell transplantation in myelodysplastic syndrome with severe coronary artery disease. 1651 35

In small bowel transplantation (SBTx), graft-versus-host disease (GVHD) is mediated by donor-derived T cells recognizing host major histocompatibility complex (MHC) alloantigens, and represents an important immunological event influencing life in experimental and clinical situations. We evaluated the possibility that a new sphingosine 1-phosphate receptor agonist, FTY720, could diminish GVHD in a rat SBTx model through traffic alteration of donor-derived T cells in target organs. Heterotopic SBTx was performed using a parent (WF)-into-F(1) (WF x ACI) rat combination. Recipient survival, body weight, histopathology, donor-derived T cell subpopulation and cytokine production were compared with untreated controls. FTY720 inhibited lethality and histopathological changes in target organs when administered at 0.5 mg/kg, possibly due to sequestration of donor-derived T cells in the intestinal graft. FTY720 caused a significant reduction in donor T cell numbers in target organs by promoting these cells to home into donor, but not recipient, secondary lymphoid tissues. FTY720 significantly decreased production of interferon (IFN)-gamma in target organs. These findings indicate that FTY720 effectively reduced recirculation of activated donor-derived T cells and recruitment to target organs in GVHD, and was also associated with down-regulated IFN-gamma production. These properties may offer the potential to treat ongoing GVHD in SBTx.
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PMID:Inhibition of donor-derived T cells trafficking into target organs by FTY720 during acute graft-versus-host disease in small bowel transplantation. 1696 2

Interleukin (IL)-7 promotes both thymopoiesis and mature T lymphocyte survival and proliferation in experimental murine models of hematopoietic stem cell (HSC) transplantation. Because HSC products for transplantation also may contain IL-7-responsive mature T lymphocytes, we examined whether IL-7 is necessary for the induction of GVHD after allogeneic bone marrow transplantation (BMT). Lethally irradiated C57BL6J (B6) and B6.IL-7(-/-) (both H2K(b)) recipient mice were co-transplanted with T cell-depleted (TCD) bone marrow cells and lymph nodes (LNs) from either congenic B6.SJL (CD45.1(+)) or allogeneic BALB/c (H2K(d)) donor mice. After transplantation, the recipient mice were subcutaneously injected with either human recombinant IL-7 or phosphate-buffered saline (PBS) for 60 days. No evidence of GVHD was detected in the congenic recipients or in the allogeneic B6/IL-7(-/-) recipients treated with PBS; in contrast, significantly increased rates of GVHD-related mortality and morbidity were found in the allogeneic B6.IL-7(-/-) recipients treated with IL-7. The proliferation and number of donor T cells were significantly lower at day 30 post-BMT in the PBS-treated B6.IL-7(-/-) recipients compared with the IL-7-treated B6.IL-7(-/-) mice. These experiments demonstrate that IL-7 is an important factor in the development of GVHD, presumably by supporting the survival, proliferation, and possibly activation of alloreactive donor-derived T cells in the recipients.
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PMID:Importance of interleukin-7 in the development of experimental graft-versus-host disease. 1815 57

This study delineates specific functions of Galphai2 and Galphai3 in T cell mobilization during the development of graft-versus-host disease (GVHD) and reveals reciprocal effects of these two G proteins on the onset and morbidity of the disease. A deletion of Galphai2 hampered trafficking of pathogenic T cells from secondary lymphoid tissues to inflammatory sites and sufficiently prevented GVHD. In contrast, a severer disease was induced in mice adoptively transferred with Galphai3-deficient T cells than those mice transferred with wild-type T cells. In agreement with this, pathogenic Galphai2(-/-) T cells displayed a defect in response to CXCL10, CXCL11, and CCL5, whereas lack of Galphai3 augmented T effector cell chemotaxis induced by CXCL10 and CXCL11 and resulted in their preference of homing to the liver and colon. Absence of either Galphai also abrogated sphingosince-1-phosphate (S1P)-mediated inhibition of T cell chemokinesis and facilitated T cell homing and expansion in the spleen and mesenteric lymph nodes at the early phase of GVHD development, which is another key determinant in the severity and early onset of the disease in the mice infused with Galphai3(-/-) T cells. These observations underscore interplay between Galphai2 and Galphai3 and potentially provide a novel strategy to prevent GVHD by blocking T cell homing at early stages and T effector cell trafficking at later time points.
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PMID:Reciprocal function of Galphai2 and Galphai3 in graft-versus-host disease. 1852 56


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