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)

The beneficial effect of deoxyspergualin (DSG, NKT-01) on lethal graft-versus-host disease in mice has been studied in a major histoincompatible donor-recipient combination. Suppression of the effector mechanisms responsible for the lethal outcome in this GVHD model is also noted. This study reveals: (1) DSG has a marked potential for treatment of lethal GVHD; (2) DSG and methotrexate in combination yield longer survival times than DSG or MTX alone; (3) long-term survivors, following DSG treatment, become stable chimeras as evidenced by cell-surface analysis of spleen cells; and (4) high activity of H-2-reactive cytotoxic T lymphocytes is detected in spleens of the mice with lethal GVHD, whereas natural killer activity is only slightly increased. DSG inhibits CTL activity not only in the induction stage but also in the advanced stage of the disease. These findings indicate that DSG might be beneficial in clinical bone marrow transplantation either alone or in combination with MTX.
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PMID:Deoxyspergualin in lethal murine graft-versus-host disease. 200 30

T cells with natural killer cell phenotype and function (NKT cells) have been described in both human and murine tissues. In this study, culture conditions were developed that resulted in the expansion of CD8(+) NKT cells from bone marrow, thymus, and spleen by the timed addition of interferon-gamma (IFN-gamma), interleukin 2 (IL-2), and anti-CD3 monoclonal antibody. After 14 to 21 days in culture, dramatic expansion of CD3(+), CD8(+), alphabetaT-cell receptor(+) T cells resulted with approximately 20% to 50% of the cells also expressing the NK markers NK1.1 and DX5. The CD8(+) NKT cells demonstrated lytic activity against several tumor target cells with more than 90% lysis by day 14 to day 21 of culture. Cytotoxicity was observed against both syngeneic and allogeneic tumor cell targets with the greatest lytic activity by the cells expressing either NK1.1 or DX5. The expanded CD8(+) NKT cells produce T(H)1-type cytokines with high levels of IFN-gamma and tumor necrosis factor alpha. Expansion of the CD8(+) NKT cells was independent of CD1d. Ly49 molecules were expressed on only a minority of cells. A single injection of expanded CD8(+) NKT cells was capable of protecting syngeneic animals from an otherwise lethal dose of Bcl1 leukemia cells. Expanded CD8(+) NKT cells produced far less graft-versus-host disease (GVHD) than splenocytes across major histocompatibility barriers, even when 10 times the number of CD8(+) NKT cells as compared to splenocytes were injected. This reduction in GVHD was related to IFN-gamma production since cells expanded from IFN-gamma knock-out animals caused acute lethal GVHD, whereas cells expanded from animals defective in fas ligand, fas, IL-2, and perforin did not. These data indicate that CD8(+) NKT cells expanded in this fashion could be useful for preserving graft-versus-leukemia activity without causing GVHD.
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PMID:Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. 1134 13

It is known that the liver is a major hematopoietic organ at fetal stages, but the hematopoiesis of this organ ceases at birth. However, the liver is still found to comprise c-kit+ stem cells and gives rise to extrathymic T cells, NK cells, and even granulocytes after birth. Extrathymic T cells generated in the liver of mice are identified as intermediate TCR (TCRint) cells, which include the NK1.1+TCRint (i.e. NKT cells) and NK1.1-TCRint subsets. Although extrathymic T cells are few in number during youth, they increase in number with advancing age. The number and function of extrathymic T cells are also elevated under conditions of stress, infections, malignancy, pregnancy, autoimmune diseases, chronic GVH diseases, etc. Under these conditions, the mainstream of T cell differentiation in the thymus, which produces conventional T cells, is inversely suppressed. Extrathymic T cells comprise self-reactive forbidden clones and mediate cytotoxicity against abnormal self-cells. Therefore, they might be beneficial for the elimination of such cells. However, over-activation of extrathymic T cells might be responsible for the onset of certain autoimmune diseases.
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PMID:Extrathymic pathways of T cell differentiation. 1134 23

Chronic graft-versus-host disease (GVHD) accompanying autoimmune disease was induced in (C57BL/6xDBA/2) F(1) mice (H-2(b/d)) by an injection of splenic T cells of parental DBA/2 origin (H-2(d)). In parallel with the onset of proteinuria, an expansion of lymphocytes was induced in the liver and kidney, showing a peak at 2 weeks after the onset of disease. The majority of lymphocytes were of recipient origin (H-2(b/d)). The main lymphocyte subset among T cells at the pre-onset stage and after the onset of disease was CD8(+) NK1.1(-) CD3(int) cells (of extrathymic, hepatic origin) in both the liver and kidney. NK1.1(-) CD3(int) cells confer primarily neither NK-like nor NKT-like cytotoxicity. No induction of these types of cytotoxicity was observed in these mice with the expansion of NK1.1(-) CD3(int) cells. This raised the possibility that granulocytes induced in the liver and kidney might be associated with tissue damage. The present results suggest that, similarly to the case of autoimmune-prone mice with genetic background (e.g. MRL-lpr/lpr mice and BXSB mice), NK1.1(-) CD3(int) cells of extrathymic, hepatic origin might be crucial lymphocytes involved in the induction of the autoimmune-like disease in mice with chronic GVHD, in conjunction with Bcells (e.g. B-1 cells).
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PMID:Unconventional NK1.1(-) intermediate TCR cells as major T lymphocytes expanding in chronic graft-versus-host disease. 1220 36

Alfa-Galactosyl Ceramide was isolated from Ocean sponge which has antitumor effect against several tumors in in vivo animal model with no cytotoxicity. KRN7000(KRN) is the most potent alpha-Galactosyl Ceramide modified from the one isolated from Ocean sponge. KRN is also active against metastatic tumors through the activation ofanimal immune system. Research efforts in learning the mechanism of action, we found the important role of dendritic cells(DC) and NKT cells. NKT cells was first characterized in 1988 which is overlap some part with NK cells and T-Cells and majority is different from NK and T. KRN is active through the activation of DC and NKT in giving antigen specific immune stimulation in animal. This antigen specific stimulation is memorized by immune system and can reject second tumor challenge. KRN is not active in nude mice and NKT deficient animal. NKT cells level in blood is lower in patients with autoimmune disease, cancer, HIV positive or aplastic anemia. NKT rapidly releases IL-4 and IFN-gamma at high level when activated. NKT is CD1d and TCR restricted. NKT plays important role in autoimmune disease such as Type 1 Diabetes, Scleroderma and Systemic Lupus Erythematosus, infections such as Mycobacteria, Listeria and Malaria, GVHD control and tumor rejection. NKT acts as double edge sword, aggressive and suppressive ways. KRN can prevent the onset of Type 1 Diabetes, inhibit replication of hepatitis virus B in liver and suppress malaria replication in activating NKT cells. KRN can activate NKT through DC and activated NKT activates NK, T and macrophage. KRN also expands NKT cells and expanded NKT has full function. Although the exact role of DC and NKT is not clear, KRN clinical study results in conjunction with DC and NKT cell activation are expected.
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PMID:Role of NKT cells and alpha-galactosyl ceramide. 1243 Aug 64

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

We have studied the influence of cell subsets [CD34, CD3, CD4, CD8, CD14, CD20, natural killer (NK; CD3(-)/CD56(+)), NKT (CD3(+)/CD56(+)), DC1, and DC2 cells] of granulocyte colony-stimulating factor mobilized peripheral blood stem cells (PBSC) on early T-cell chimaerism and later clinical outcomes in 125 patients with haematological malignancies who received human leucocyte antigen (HLA)-matched related grafts after non-myeloablative conditioning. Conditioning consisted of 2 Gy total body irradiation (TBI) alone (n = 28), or 2 Gy TBI preceded by either 90 mg/m(2) fludarabine (n = 62) or planned autologous haematopoietic cell transplantation (HCT) (n = 35). Post-transplant immunosuppression included mycophenolate mofetil and ciclosporin. Multivariate analysis showed that higher numbers of grafted NK cells predicted higher early T-cell chimaerism (P = 0.03), while higher numbers of B cells were associated with better clinical outcomes and a higher risk for chronic graft-versus-host disease (P = 0.05). Higher numbers of CD14(+) cells were associated with worse overall survival (P = 0.03), while higher numbers of CD34(+) cells showed better survival (P = 0.03). The addition of fludarabine or autologous HCT predicted higher early T-cell chimaerism (P = 0.001), while advanced donor age predicted lower chimaerism (P < or = 0.02). Patients with aggressive diseases were at higher risk for relapse/disease progression, and shorter progression-free and overall survival (P < 0.01). These results suggest that the dosing of certain cellular subsets of PBSC products can influence important outcomes post-HCT after non-myeloablative conditioning.
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PMID:Allogeneic peripheral blood stem cell graft composition affects early T-cell chimaerism and later clinical outcomes after non-myeloablative conditioning. 1572 88

NKT cells have pivotal roles in immune regulation and tumor immunosurveillance. We report that the G-CSF and FMS-like tyrosine kinase 3 ligand (Flt-3L) chimeric cytokine, progenipoietin-1, markedly expands the splenic and hepatic NKT cell population and enhances functional responses to alpha-galactosylceramide. In a murine model of allogeneic stem cell transplantation, donor NKT cells promoted host DC activation and enhanced perforin-restricted CD8+ T cell cytotoxicity against host-type antigens. Following leukemic challenge, donor treatment with progenipoietin-1 significantly improved overall survival when compared with G-CSF or control, attributable to reduced graft-versus-host disease mortality and paradoxical augmentation of graft-versus-leukemia (GVL) effects. Enhanced cellular cytotoxicity was dependent on donor NKT cells, and leukemia clearance was profoundly impaired in recipients of NKT cell-deficient grafts. Enhanced cytotoxicity and GVL effects were not associated with Flt-3L signaling or effects on DCs but were reproduced by prolonged G-CSF receptor engagement with pegylated G-CSF. Thus, modified G-CSF signaling during stem cell mobilization augments NKT cell-dependent CD8+ cytotoxicity, effectively separating graft-versus-host disease and GVL and greatly expanding the potential applicability of allogeneic stem cell transplantation for the therapy of malignant disease.
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PMID:NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs. 1622 35

Interferon (IFN)-gamma, a potent proinflammatory cytokine produced by multiple types of cells (e.g., activated T, NK and NKT cells), plays important and complex roles in both innate and adaptive immune responses. There may be a correlation between the IFNgamma level and GVHD severity in patients receiving allogeneic hematopoietic cell transplantation. However, such a correlation may just reflect the presence of large numbers of activated T cells, and does not necessarily imply a harmful role of IFN-gamma in the pathogenesis of GVHD. There has been increasing experimental evidence that IFN-gamma is not required and may even inhibit GVHD. Paradoxically, IFN-gamma facilitates graft-versus-leukemic (GVL) effects. Thus, IFN-gamma blockade is likely deleterious in patients after allogeneic hematopoietic cell transplantation, and not beneficial as previously suggested.
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PMID:Role of Interferon-gamma in GVHD and GVL. 1636 58

Our previous works indicate that regulatory cells such as natural killer (NK) cells and NKT cells could play an active role in maintaining the remission state of MS. We have therefore adopted a strategy for developing the future MS therapy by targeting NKT cells. The unique glycolipid-reactive lymphocytes are known to produce a large quantity of Th2 cytokines such as IL-4 when encountering their ligands like alpha-galactosylceramide (alpha-GC). Whereas most of the NKT ligands so far described would stimulate both Th1 and Th2 cytokine production by NKT cells, the synthetic compound OCH, an analogue of alpha-GC with a shorter lipid tail, is the one which selectively induces IL-4 production. Given this property, oral or intraperitoneal OCH administration would prohibit the development of a variety of Th1-meediated pathology, including EAE, collagen-induced arthritis, type 1 diabetes, DSS-induced colitis and acute GVHD by inducing Th2 bias. This review paper summarizes the recent publications and our unpublished results related to the efficacy of OCH and to the molecular mechanism accounting for the Th2 inducing property of OCH.
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PMID:[Synthetic glycolipid ligands as novel therapeutics for multiple sclerosis]. 1644 60


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