Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Recent studies have demonstrated that the treatment of mice with anti-gp39 antibodies impairs T-cell functions in the murine collagen type II-induced arthritis model, in acute semi-allogenic graft-versus-host disease, and in the allo-specific CTL-reaction, that is, reactions that are believed to be mediated by Th1-type T cells. On the other hand, the administration of anti-gp39 antibody did not influence Th2 T-cells responses, suggesting that CD40-CD40L interactions are more crucial for Th1 than Th2 T-cell development. Recent studies also demonstrate that dendritic cells (DC) are capable of driving a Th1 T-cell response that is mediated by IL-12. In addition, stimulation of CD40 on human monocytes results in IL-12 production, suggesting that activated T cells expressing CD40L may directly induce the production of IL-12 by antigen-presenting cells, thus allowing for the generation of a Th1 T-cell response in the absence of intracellular pathogens. We investigated whether the CD40-CD40L interaction was important in the production of IL-12 by DCs in an in vitro system that allowed precise control of cytokine concentrations. Initially we showed that FACS-purified mouse spleen DCs produce high amounts of IL-12 p40 in response to CD40 crosslinking by CD40L-expressing fibroblasts. We then demonstrate that DCs also produce IL-12 p40 in a more physiologic system using purified DCs pulsed with ovalbumin (OVA) and then cultured with LECAM-1hi T cells from ovalbumin T-cell receptor transgenic mice. Finally, we show that IL-10 has a potent capacity to shut down CD40-induced IL-12 p40 secretion; and, in addition, IL-4 partially inhibits CD40-induced IL-12 p40 secretion and enhances IL-10-mediated inhibition in an additive fashion. We also investigated the in vivo relevance of this interaction in an experimental model for a Th1-mediated disease, the hapten reagent (TNBS)-induced colitis. The administration of anti-gp39 (CD40L) antibodies during the induction phase of the Th1 response completely prevented IFN-gamma production by CD4 T cells from the intestinal lamina propria and also the clinical and histological evidence of disease. In further studies we showed that the prevention of disease activity was due to an inhibition of IL-12 secretion. Thus, the injection of recombinant IL12 p75 heterodimer into TNBS + anti-gp39-treated mice reversed the effect of anti-gp39 and resulted in severe disease activity. In conclusion, these findings suggest that DCs produce IL-12 in response to CD40 signaling, that a mechanism by which IL-4 may induce Th2 development is by acting with IL-10 to inhibit IL-12 production by DCs, and that the CD40L-CD40 interaction is crucial for the IL-12-dependent priming of Th1 T cells in vivo.
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PMID:Interleukin-12 production by dendritic cells. The role of CD40-CD40L interactions in Th1 T-cell responses. 895 22

Hematopoietic progenitor and stem cells are contained within the CD34+ cellular compartment of the bone marrow. Positively selected cytokine primed peripheral blood derived CD34+ cells have been shown to support autologous hematopoiesis after myeloablative therapy. We investigated hematologic reconstitution and incidence of graft-versus-host disease (GVHD) after transplantation of allogeneic peripheral blood CD34+ cells. CD34+ cells were selected from the peripheral blood of 10 matched related donors after treatment with rG-CSF followed by one to four apheresis procedures and biotin-avidin immune affinity purification. Ten patients with advanced hematologic malignancies were subsequently transplanted with cryopreserved allogeneic CD34+ cells after myeloablative chemotherapy. Immune affinity purification of CD34+ cells resulted in a 370-fold T cell reduction. Patients were grafted with a median number of 4.1 x 10(6) kg (1.6-6.4) CD34+ cells and 0.42 x 10(6)/kg (0.29-2.2) CD3+ cells. All patients received rG-CSF 5 micrograms/kg post-transplant and completely engrafted with neutrophils > 500/microliter after a median time of 10 days (9-15) and platelets > 20,000/microliter after 16 days (10-74). Complete donor chimerism was demonstrated by cytogenetic and molecular methods up to day +385 post-transplant. Cyclosporin A only was used for GVHD prophylaxis. Four of 10 patients developed acute GVHD with grade I (one) and II (three) which completely resolved with treatment. Two patients died from infectious complications. Three patients died from relapse or progressive disease. Five patients are alive in remission without GVHD with a median follow-up time of 254 (93-457) days and three of five are without immunosuppression. Allogeneic transplantation of positively selected peripheral blood-derived CD34+ cells is feasible and safe and leads to long-term engraftment without severe GVHD suggesting that peripheral blood-derived CD34+ cells contain pluripotent hematopoietic stem cells. The reduced number of T cells transplanted appears to be sufficient for engraftment.
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PMID:Allogeneic transplantation of positively selected peripheral blood CD34+ progenitor cells from matched related donors. 897 76

Despite improved procedures in chemotherapy and bone marrow transplantation (BMT), post-BMT leukemia relapse rates have remained rather constant in the last decade. Immunotherapy with monoclonal or bispecific antibodies (bsAb) is a promising approach to improve this situation, but is hampered by the absence of tumor-specific antigens on the majority of tumors. To evade this problem, we developed a new tumor-specific approach in which bispecific antibodies exploit chimerism after allogeneic BMT by redirecting donor T cells against recipient-specific antigens on tumor cells. Two different leukemia relapse models were established using a T-cell lymphoma (ST-1) and a B-cell lymphoma (BCL1) to evaluate the efficiency of such a therapy. In these experiments, irradiated BALB/c (Thy-1.2+, I-Ad) mice were transplanted with C57BL/6 Thy-1.1 (I-Ab) BM cells under the protection of graft-versus-host disease-preventing monoclonal antibodies. Forty-five days after BMT, the chimeric mice were injected with either 2 x 10(4) recipient-type, Thy-1.2+, CD3- ST-1 cells or major histocompatability complex (MHC) class II+ (I-Ad)-BCL1 cells. Four days later, the mice were treated with 8 microg bsAb G2 (anti-CD3 x anti-Thy-1.2) or 10 microg (+10 microg, day 6) bsAb BiC (anti-CD3 x anti-I-Ad), respectively. These combinations guaranteed exclusive binding of the bsAbs target arms to tumor cells, leaving the surrounding, donor-type hematopoietic cells unbound. Compared with the parental antibodies, the bsAbs markedly reduced tumor mortality. Between 34% and 83% of mice survived in the bsAb groups compared with 0% of the control groups treated with parental antibodies, clearly documenting the benefit of the redirection principle. Furthermore, cytokine release (interleukin-6) after anti-CD3 antibody or bsAb treatment was decreased by administering a low-dose antibody preinjection. We have shown (1) that 6 weeks after BMT, when donor T-cell reconstitution is still in progress, T-cell-redirecting bsAb are clearly superior to parental antibodies in terms of tumor cell elimination; and (2) that the polymorphism of a common antigen such as Thy-1 or a clinically more relevant target antigen such as MHC class II can be used as an operational tumor-specific antigen after allogeneic BMT.
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PMID:Bispecific antibodies target operationally tumor-specific antigens in two leukemia relapse models. 897 58

Peripheral blood stem cells (PBSCs) are gaining increasing acceptance as an alternative to bone-marrow (BM)-derived stem cells for allografting. Although scarce under steady-state conditions, CD34+ progenitor cells can be effectively mobilized into the peripheral blood (PB) in the vast majority of normal donors with a brief (3-4 days) course of recombinant human (rHu)G-CSF. Those cytokine-peripheralized progenitor cells and, among them, pluripotent stem cells, are collected by apheresis in sufficient amounts to achieve complete and permanent alloengraftment after myeloablative treatment in patients with primarily malignant hematologic disorders. The short-term tolerability profile of PBSC mobilization and apheresis in normal donors appears to be acceptable, although continued monitoring is necessary to ensure long-term safety. When compared with BM progenitor cells, mobilized PBSCs seem to exhibit a more primitive phenotype and a different clonogenic potential. The impact of factors affecting the efficiency of PBSC mobilization, such as rHuG-CSF dose, duration of cytokine treatment, and, to a lesser extent, donor age is now being recognized. Potential ways to optimize and possibly "engineer" PBSC collection, such as the use of cytokine/chemokine combinations (e.g., thrombopoietin, stem cell factor, etc.) and monoclonal antibodies directed against integrin receptors on CD34+ progenitor cells, are now being explored as well. In the clinical setting, engraftment after PBSC allografting is rapid and probably faster than after BM allografting. PBSC allografting seems to be associated with an incidence and severity of acute graft-versus-host disease (GVHD) comparable to the ones observed after BM allografting, although the incidence of chronic GVHD after allogeneic PBSC transplantation is still controversial. The infusion of a larger number of lymphoid cells appears to translate into a more rapid immunologic recovery and may lead to an enhanced graft-versus-leukemia effect. The collection of large numbers of mobilized PBSCs should provide ample opportunities for graft engineering and gene therapy. PBSCs may eventually replace, at least in part, BM as the preferred source of stem cells for both auto- and allotransplantation.
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PMID:The use of mobilized peripheral blood stem cells from normal donors for allografting. 900 18

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

Graft-versus-leukemia (GVL) effect is an immunologically important phenomenon which decreases the relapse rate of leukemia after allogeneic bone marrow transplantation. GVL effect is sometimes associated with the occurrence of graft-versus-host disease (GVHD). Analyses of GVL effect and GVHD showed that these two phenomena were separable in some conditions. Although we cannot yet completely control the development of the GVL effect without inducing GVHD in humans, basic analyses using animal models show potential benefits of the GVL effect for clinical applications. Autologous GVHD is another important phenomenon which can help to eradicate minimal residual disease. Interleukin 2 and/or cyclosporin A are extensively used in animal models and in humans to induce autologous GVHD, showing beneficial effects. In the future, cytokine usage and allogeneic stem cell transplantation or leukocyte infusion appear to be promising in the control of minimal residual disease. Further studies on the mechanisms of GVL effects and GVHD may well open a new era for cell transplantation.
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PMID:Graft-versus-leukemia effect and its clinical implications. 903 Oct 79

The significance and potency of GVL can no longer be argued. It is very clear that an allogeneic bone marrow graft provides an important GVL component critical to the success of BMT for many patients. The extraordinary success of donor MNC infusions to treat relapse after BMT shows that it is now possible to manipulate the GVL reaction to treat leukemia. The identity of the effector cells and target antigens remains unclear, but no doubt future experiments will begin to dissect out the complex cellular and cytokine interactions that mediate GVL reactivity. It also remains unclear whether GVL is distinct from GVHD; ultimately, the ability to harness GVL without excessive toxicity from GVHD will be a central challenge in BMT and cellular immunotherapy. There is now an excellent opportunity to understand the detailed mechanisms of GVL and to begin to design clinical strategies to harness the potent GVL effects of allogeneic donor cells for greater therapeutic benefit.
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PMID:Graft-versus-leukemia effect of allogeneic bone marrow transplantation and donor mononuclear cell infusions. 907 98

We have investigated cytokine mRNA expression in the peripheral blood mononuclear cells of 20 patients who received allogeneic hematopoietic stem cell transplants to assess the cytokine network after transplantation. IL-4 mRNA expression decreased in five of five (100%) patients with > or = grade III (severe) acute GVHD and increased in 10 of 22 (45%) patients without severe GVHD. In contrast, IL-12 mRNA expression increased in two of two (100%) patients with severe GVHD, but increased in only six of 18 (33%) patients without severe GVHD. Furthermore, IL-10 and/or IL-13 mRNA expression increased in 19 of 22 (86%) patients without severe GVHD, but increased in only one of three (33%) patients with severe GVHD. In patients with allogeneic PBSCT who had severe acute GVHD, the cytokine mRNA expression in patients with allogeneic PBSCT, who had no severe GVHD, showed a similar pattern to that in patients with allogeneic BMT. IL-4 mRNA expression increased in three of five (60%) patients and IL-10 and/or IL-13 mRNA expression increased in five of five (100%) patients. In contrast, IL-12 mRNA expression increased in only one of three (33%) patients. Serum IL-4 concentration in allogeneic PBSCT patients in the early engraftment phase was relatively high, while serum IL-12 concentration was low. These findings suggest that severe GVHD may be related to the cytokine imbalance between type 1 helper T (Th1) cells and type 2 helper T (Th2) cells.
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PMID:The important balance between cytokines derived from type 1 and type 2 helper T cells in the control of graft-versus-host disease. 908 37

Chronic graft-versus-host disease (GVHD) is thought to result from abnormalities of several cytokine regulations in vivo. We analyzed interleukin-5 (IL-5) production by peripheral lymphocytes in a patient showing hypereosinophilia associated with chronic GVHD after allogeneic bone marrow transplantation. IL-5 production by activated T-lymphocytes which are known to play a major role in chronic GVHD was upregulated when stimulated by PMA + ionomycin. Therefore, hypereosinophilia observed in our patient may be correlated with IL-5 production in donor T-lymphocytes.
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PMID:[Hypereosinophilia after allogeneic bone marrow transplantation. A possible role of IL-5 overproduction by donor T-cells chronic GVHD]. 909 65

The existence of functionally polarized human T cell responses based on their profile of cytokine secretion in both the CD4+ T helper (Th) and the CD8+ T cytotoxic cell subset has been established. Human Th1 and Th2 cells not only produce a different set of cytokines but also exhibit distinct functional properties and preferential expression of some activation markers, such as LAG-3 and CD30, respectively. Several factors are involved in the Th cell differentiation into the polarized Th1 or Th2 pathway. They include the cytokine profile of 'natural immunity' evoked by different offending agents, the nature of the peptide ligand, as well as the activity of some costimulatory molecules and microenvironmentally secreted hormones, in the context of different host genetic backgrounds. Polarized Th1-type and Th2-type responses play different roles in protection, Th1 being effective in the defense against intracellular pathogens and Th2 against intestinal nematodes. Moreover, they are responsible for different types of immunopathological reactions. Th1 responses predominate in organ-specific autoimmune disorders, acute allograft rejection, unexplained recurrent abortions, and in some chronic inflammatory disorders of unknown etiology. In contrast, Th2 responses predominate in Omenn's syndrome, transplantation tolerance, chronic graft versus host disease, systemic sclerosis; moreover allergen-reactive Th2 cells are involved in the triggering of atopic disorders.
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PMID:An update on human Th1 and Th2 cells. 913 May 8


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