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)

Immunotherapy can be defined as treatment directed at augmenting host immune defence mechanisms. Non-antimicrobial therapies and immunoprophylaxis in bone marrow transplantation (BMT) can be subdivided into three broad categories: passive immunotherapy with intravenous immunoglobulin (IVIG); cytokine therapy; and anti-endotoxin-directed treatments. Most studies using IVIG in BMT are prophylactic and suffer from variability in study design, type of IVIG and dosing regimens. Various effects on viral and bacterial infections and graft-versus-host disease (GVHD) have been reported but few if any have shown benefit in terms of improved patient survival. Moreover the immunomodulatory effect of immunoglobulin G preparations is frequently overlooked. With the exception of cytomegalovirus (CMV) pneumonitis, there is little evidence of benefit in the treatment of established infections and the relative benefits of hyperimmune preparations are poorly established. The development of haemopoietic growth factors has led to the widespread use of cytokines in BMT. The benefits of these agents both in the prevention of fever and infection and as adjuvants to standard antimicrobial therapy in established infection (e.g. invasive mycoses) are rapidly becoming apparent. Both human recombinant granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and granulocyte colony-stimulating factor (rhG-CSF) have been shown to accelerate granulocyte recovery following BMT and reduce fever days, antibiotic usage and hospitalization. RhGM-CSF appears superior in these respects. The roles of interleukin 1 (IL1), IL3, IL6 and interferons are also under evaluation. As with the much publicised studies using anti-endotoxin antibodies as therapy in sepsis, there is little evidence of benefit in the few studies performed in BMT patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immunotherapy and immunoprophylaxis in bone marrow transplantation. 756 Sep 54

Interleukin-6 (IL-6) induced increased, leukocyte and platelet counts on around day 20 when it was administered into [BALB/c-->C3H/He] bone marrow chimeras from day 1 to day 12. Increased leukocyte counts and hemoglobin (Hb) levels were also observed at around day 60 and from day 41 to 80, respectively. On the other hand, hematopoietic recovery in [C3H/He-->C3H/He] bone marrow chimeras injected with IL-6 was different from that in [BALB/c-->C3H/He] bone marrow chimeras, showing no delayed and long-lasting increase in Hb levels but showing an early and transient increase in Hb levels and platelet counts. Sera from [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 showed predominant productions of IL-3 and/or IL-4. Reverse transcriptase polymerase chain reaction (RT-PCR) showed that stem cell factor (SCF) mRNA expression was increased in bone marrow or spleen cells from [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 on day 36. Furthermore, we analyzed influence of IL-6 on graft-versus-host disease (GVHD) in [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6. Decreased survival days and body weights were not observed when compared with the control. Histopathological changes of the liver due to GVHD were also not obvious. However, alloreactive mixed lymphocyte reactions (MLRs) were readily detected although cytotoxic T cells were not generated. Since H-2 typing showed that donor-type chimerism was predominantly observed, it was suggested that split tolerance might be induced by IL-6 administration. Increased IL-2 levels were not detected in sera from [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 whereas IL-4 was detected in the same sera, indicating that type 2 helper T (TH2) cells appeared to be predominantly generated. These results suggest that IL-3/IL-4 and SCF appeared to synergistically support delayed effects on hematopoiesis in [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 although early effects appeared to be mediated mainly by IL-6 directly or indirectly. Furthermore, IL-6 could induce split tolerance in [BALB/c-->C3H/He] bone marrow chimeras via a preferable activation of TH2 type cells without inducing severe GVHD.
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PMID:In vivo administration of interleukin-6 in murine allogeneic bone marrow chimeras: early and delayed enhancement of hematopoiesis accompanied with split tolerance but not with graft-versus-host disease. 798 20

Bone marrow mononuclear cell (BMMC) transplant may serve to produce donor specific tolerance for a coincident solid organ graft, but with the risk of graft versus host disease (GVHD). We examined in vitro the immunomodulatory effect of UVB on human BMMCs as potential prophylaxis against GVHD for clinical transplantation. After 10-200 J/m2 UVB-irradiation, BMMCs were examined by proliferative response (in mixed lymphocyte reaction and following phytohemagglutinin stimulation) and by cytokine profile. We also evaluated CFU-GM, CFU-GEMM, and BFU-E progenitor viability by 2-week methyl cellulose cultures following UVB-irradiation. Parallel studies were applied to marrow that was T-cell depleted by soybean agglutination (SBA) or by SBA and sheep erythrocyte rosetting (SBA-E-). We found that (1) UVB produces a dose-dependent inhibition of the proliferative response to stimulators by human BMMCs; (2) increasing doses of UVB-irradiation and increasing levels of T-cell depletion (TCD) are both inversely related to production of lymphokines (IL2, IL3, LIF, IFN-gamma, and GMCSF) and (3) T-cell depletion, but not UVB-irradiation, decreases the production of monokines (IL1, TNF, IL6). Progenitor cell viability was decreased but preserved at 100 J/m2 of UVB. Our findings suggest that UVB compares favorably with TCD as a technique for inhibition of GVHD and therefore that UVB-modulation of bone marrow (BM) inoculum may be useful in the prevention of GVHD in clinical bone marrow transplantation accompanying a solid organ graft.
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PMID:UVB-irradiation of human bone marrow: potential for donor specific tolerance. 876 77

Cord blood transplantations successfully reconstituted hemopoiesis in patients treated with myeloablative therapies. These transplantations were associated with a low rate of acute graft-versus-host disease (aGVHD), a major life-threatening complication of allo-transplantation. The physiopathology of aGVHD implies the recognition of host alloantigens by donor T cells but also involves a cytokine cascade. In this cascade, interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma) produced by donor T cells and monocytes/macrophages play a major effector role. Therefore, we investigated whether the lower percentage of aGVHD in cord blood transplants could be related to a lower ability to produce these cytokines in vitro compared with adult blood. Mononucleated cells (MNCs) isolated from term cord blood and adult peripheral blood were stimulated with a combination of lipopolysaccharide and phytohemaglutinin and incubated for 96 hours. Levels of IL-1beta, IL-2, IL-3, IL-4, IL-6, TNF-alpha, IFN-gamma, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured in the supernatants after various times of incubation. The productions of IL-1beta, IL-6, and GM-CSF were similar in stimulated cord and adult blood and IL-3 levels, though lower and delayed in cord blood, were not statistically different. On the other hand, we found markedly lower levels of IFN-gamma, TNF-alpha, and IL-4 in cord blood throughout the incubation period. The stimulated levels of IL-2 were similar in cord and adult samples throughout the first 48 hours of incubation but became significantly lower in cord blood after 72 and 96 hours. We suggest that the cytokine production pattern that characterizes cord blood could provide an explanation for the lower occurence of aGVHD following cord blood transplants.
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PMID:Comparative cytokine production by in vitro stimulated mononucleated cells from cord blood and adult blood. 901 9

We have explored the effect of IL-3 and IL-6, each alone and in combination with G-CSF, GM-CSF or IL-1, on neutrophil and platelet recovery in BALB/c mice (H-2d) given 10 Gy total body irradiation followed by 10(7) bone marrow cells and 10(6) spleen cells from C57BL6 donors (H-2b), as well as the effect of IL-3 alone and IL-6 alone on graft-versus-host disease (GVHD) and survival. Neither IL-3 alone nor IL-6 alone significantly increased the circulating absolute neutrophil count (ANC) at day 6 post transplant when compared with mice given saline injections (ANC 0.31 x 10(9)/l). G-CSF and IL-1, each alone, significantly raised the day-6 ANC (0.58 x 10(9)/l, p = 0.02; 0.67 x 10(9)/l, p = 0.007 respectively). However, IL-3, 200 ng twice daily, significantly increased the day-6 ANC when used in combination with GM-CSF (0.49 x 10(9)/l, p = 0.003) or with IL-6 (0.66 x 10(9)/l, p = 0.004), as well as with G-CSF (0.62 x 10(9)/l, p = 0.007) or with IL-1 (0.49 x 10(9)/l, p = 0.003). Apart from the combination with IL-3, IL-6 significantly raised the day-6 ANC only in combination with G-CSF (0.79 x 10(9)/l, p = 0.007). When used alone, both IL-6 and G-CSF raised the day-6 platelet count (312 x 10(9)/l, p = 0.02 and 309 x 10(9)/l, p = 0.01 respectively) compared with control mice (216 x 19(9)/l). IL-3 alone resulted in a platelet count of 303 x 10(9)/l (p = 0.06). In combination, only IL-3 with G-CSF significantly increased the value over that of saline control mice (328 x 10(9)/l, p = 0.02). IL-3 200 ng alone twice daily and IL-6 200 ng alone twice daily for 14 days post transplant resulted in survival not different from that of mice given saline injections. However, IL-3 500 ng twice daily for 14 days resulted in impaired survival and accelerated weight loss. In summary, while neither IL-3 nor IL-6 (nor GM-CSF) used alone accelerated neutrophil recovery post transplant, the combinations of IL-3 plus IL-6 and IL-3 plus GM-CSF did so. IL-6 (and G-CSF) accelerated platelet recovery post transplant, but combining IL-3 or IL-6 with the other cytokines was generally unsuccessful in this regard. Higher-dosage IL-3 appeared to accelerate graft-versus-host disease and impair survival, thus providing indirect evidence of the involvement of this cytokine in the mediation of GVHD.
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PMID:Effect of in vivo administration of IL-3 and IL-6, alone and in combination with G-CSF, GM-CSF or IL-1, on haematopoiesis, graft-versus-host disease and survival after murine haematopoietic stem cell transplantation. 938 63

Thrombocytopenia remains a significant cause of morbidity in cancer patients undergoing allogeneic bone marrow transplantation (BMT), which consumes millions each year for frequent platelet transfusions. Using a novel culture system containing appropriate cytokine(s) on a layer of normal human osteoblasts, we investigated the expansion of early megakaryocytic progenitor cells while maintaining the number of CD34+ stem/progenitor marrow cells in an attempt to provide an effective solution for the problem of post-transplant thrombocytopenia. After seven days of culture, normal human osteoblasts alone without cytokines significantly increased the number of CD34+ and CD34+CD41+ marrow cells. Among the various cytokine combinations tested, both stem cell factor (SCF), interleukin 3 (IL-3)+IL-11 and SCF+IL-3+IL-11+thrombopoietin (TPO) emerged as the most effective in expanding early CD34+CD41+ megakaryocytic cells. Early CD34+CD41+ megakaryocytic cells have increased by 3.1- and 4.7-fold compared with day 7 control cultures, and by 62- and 94-fold, respectively, compared with day 0 input, respectively. Also, late CD41+ megakaryocytic cells have increased by 15.4- and 27.5-fold compared with day 7 control cultures in the presence of the same two combinations. In addition, the same cytokine combinations achieved 17.6- and 13.3-fold increases in the number of CD34+ marrow cells after the same seven days of culture on a layer of human osteoblasts. The combination (SCF+IL-3+IL-11+TPO) achieved the highest expansion of CD34+CD41+ early megakaryocytic cells from human marrow CD34+ cells reported so far in the literature. Recently, transplantation of SCF+IL-1+IL-3+TPO ex vivo expanded megakaryocytic progenitor cells as a supplement has been shown to accelerate platelet recovery by three to five days in mice. Therefore, the clinical use of the combination (SCF+IL-3+IL-11+TPO) for ex vivo expansion of CD34+ and megakaryocytic progenitor cells from a portion of the donor's marrow harvest is warranted in allogeneic BMT. Such a protocol would accelerate platelet recovery and shorten the period of hospitalization after allogeneic BMT. The present study has confirmed the role of human osteoblasts in supporting the proliferation and maintenance of human CD34+ stem/progenitor marrow cells. Given the facilitating role of osteoblasts shown previously in several allogeneic BMT studies in mice, it is possible to envisage a future role for donor osteoblasts in clinical BMT. Transplantation of the cultured donor osteoblasts together with the ex vivo expanded CD34+ marrow cells as a supplement might not only accelerate platelet recovery but also prevent acute graft-versus-host disease in allogeneic BMT. The present novel culture system should have useful clinical application in allogeneic BMT.
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PMID:Cytokine-induced expansion of human CD34+ stem/progenitor and CD34+CD41+ early megakaryocytic marrow cells cultured on normal osteoblasts. 1019 69

Hematopoietic xenografts were carried out in three experiments using goat fetal liver (44-48 days, experiments I and II) or purified human CD 34+ cells (experiment III) as the donor cells. Recipients were sheep fetuses at 41-47 days of gestation. Goat fetal liver cells were either injected without any pretreatment or stimulated by preincubation in a culturing in goat phytohemagglutinin-stimulated lymphocyte supernatant. Human CD 34+ myeloid progenitor cells were purified from bone marrow by minimacs immunomagnetic purification and cultured in medium supplemented with stem cell factor, IL3, and IL6. Goat-sheep chimerism was assessed by flow cytometry analysis (FCA) of peripheral blood and bone marrow cells using a mouse anti-goat CD 45 monoclonal antibody and by karyotype analysis of peripheral blood from goat/sheep chimeras. Human cell engraftment was assessed by polymerase chain reaction amplification of the human DAX1 gene in blood and bone marrow DNA from sheep which had received human cells. In the three experiments, a mean of 76% (26 of 34) of injected fetuses were born alive without any clinical evidence of graft-versus-host disease. Three lambs were found to be goat/sheep chimeric after flow cytometry analysis (peripheral blood and bone marrow) and karyotype (peripheral blood) analysis. Both tissues continued to express goat cells at 6 or 12 months (last assessment) depending on the experiment. No human chimerism was detected using polymerase chain reaction amplification in peripheral blood and bone marrow of any of the six sheep grafted with human cells. These data and those also obtained on other species (human, pig/sheep) show that it is possible to carry out hematopoietic xenografts using the sheep fetus as recipient provided both donor and recipient fetal cells are processed during the period of tolerance to foreign antigens.
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PMID:The xenotransplantation of goat and human hematopoietic cells to sheep fetuses. 1022 82

Scleroderma (SSc) is a fibrosing connective tissue disease that is poorly responsive to any treatment, including immune suppression. SSc shares many characteristics with chronic graft-versus-host disease (GVHD). Because the immunomodulatory drug thalidomide has proven beneficial in chronic GVHD, we studied the immune response and clinical effects of thalidomide in SSc patients. We treated 11 SSc patients with thalidomide in an open label, dose escalating, 12 week study. Histologic comparison of skin biopsies showed changes in skin fibrosis and an increase in epidermal and dermal infiltrating CD8(+) T cells with thalidomide treatment. In thalidomide-treated SSc patients, plasma levels of IL-12 and TNF-alpha increased, while plasma IL-5 and IL-10 levels remained unchanged. These changes were associated with clinical effects, including dry skin, dermal edema, transient rashes, decreased gastroesophageal reflux symptoms, and healing of digital ulcers. When SSc PBMCs activated by anti-CD3 mAb were exposed to thalidomide, increases in both production of IL-2, IL-3, GM-CSF, and IFN-gamma and T cell expression of CD40L were observed. Thalidomide therefore appears to induce immune stimulation in SSc patients in association with clinical changes. However, it remains to be shown whether long-term enhancement of immune responses in SSc patients is clinically beneficial.
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PMID:Immune stimulation in scleroderma patients treated with thalidomide. 1102 51

The cellular and molecular mechanisms underlying the blunted allo-responsiveness of umbilical cord blood (UCB) T cells have not been fully elucidated. Protein expression of NFATc2 (nuclear factor of activated T cells c2), a critical transcription factor necessary for up-regulation of multiple cytokines known to amplify T-cell allogeneic responses, is reduced in UCB T cells. Affymetrix oligonucleotide microarrays were used to compare gene expression of primary purified CD4+ UCB T cells to adult peripheral blood CD4+ T cells (AB) at baseline, 6, and 16 hours of primary stimulation. NFAT-regulated genes exhibited lower expression in UCB CD4+ T cells including the following: granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin 3 (IL-3), IL-4, IL-5, IL-13, IL-2 receptor alpha (IL-2Ralpha; CD25), CD40L, and macrophage inflammatory protein 1 alpha (MIP-1alpha). Transcription factors involved in the NFAT pathway including C/EBPbeta, JunB, and Fosl1 (Fra-1), as well as Th1- and Th2-related transcription factors STAT4 (signal transducers and activators of transcription 4), T-bet, and c-maf showed reduced expression in UCB compared with AB during primary stimulation. Reduced cytokine, chemokine, and receptor expression was also found in UCB. Gene array data were confirmed using RNase protection assays, flow cytometry, and quantitative multiplexed cytokine measurements. Reduced global expression of NFAT-associated genes, as well as cytokines and chemokines, in UCB CD4+ T cells may contribute to the decreased graft-versus-host disease (GVHD) observed after UCB transplantation.
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PMID:Reduced expression of NFAT-associated genes in UCB versus adult CD4+ T lymphocytes during primary stimulation. 1294 96

Umbilical cord blood stem cell transplantation (CBSCT) has made significant progress in treatment of lethal congenital or malignant disorders. Both the incidence and severity of GVHD from CBSCT were lower than that from bone marrow and peripheral blood stem cell transplantation, particularly for adult patients, but these advantages were also associated with higher rates of relapse. The immune-mediated effect of natural killer and cytotoxic T cells against residual tumor cells were shown to prevent relapse and to induce remission after bone marrow transplantation. To explore possibility of ex vivo expansion of T, NK and CD34(+) cells from umbilical cord blood, cord blood was expanded ex vivo with different combinations of cytokines, T and NK cells proliferation and differentiation were observed. CB MNCs were separated in Ficoll-Isopaque column and cultured in IMDM for 14 days with different recombinant cytokines. Cultured cells were collected and analyzed for progenitor/stem cell immunophenotyping at day 0, 3, 7, and 14 by using flow cytometry. The results indicated that all test groups cultured with different combinations of SCF, IL-3, IL-6, IL-7, IL-2 showed significant expansion of UCB MNC, compared with the group without cytokines. All test groups showed expansion effects on CD34(+) cells, CD34(+) percentage went up from 1.6% in fresh CB to the highest 11.9% in group D (SCF + IL-3, IL-6, IL-2). The CD34(+) cells peak displayed at day 7 of culture in group A and D, while in other two groups B and C appeared at day 14 of culture. The expansion multiple of CD34(+) cells in all test groups at day 7 of culture were from 10 to 50. The average value of CD3(+) T cell in fresh UCB was 18.7 +/- 4.3%, the CD3(+) T cells decreased sharply in the medium without any interleukin, while obvious increase were observed in the other test groups containing different combinations of cytokines. The maximal expansion multiple of CD3(+) T cells reached 2 times of the fresh UCB level. CD56(+) cells amounted to 3.6 +/- 1.9% of fresh UCB, CD56(+) cell number increased significantly only in medium containing IL-2. It is concluded that T cells, NK cells as well as stem/progenitor cells can be expanded in the same time from CB-MNC with the combinations of cytokines.
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PMID:Ex vivo expansion of T, NK and CD34+ cells from umbilical cord blood. 1640 84


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