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)

Bone marrow transplantation (BMT) offers potentially curable treatment for patients with high-risk hematologic malignancies. However, relapse remains the major cause for failure of autologous BMT in these diseases and of allogeneic BMT in subsets of patients with these diseases. With our current preparative regimens, relapse rates following autologous BMT are over 30% for patients with intermediate or high-grade non-Hodgkin lymphoma and relapsed Hodgkin's disease in sensitive relapse and over 50% following autologous BMT for patients with acute non-lymphoblastic leukemia (ANLL) and acute lymphoblastic leukemia (ALL). Relapse rates exceed 80% in patients treated with autologous BMT for non-Hodgkin lymphomas and Hodgkin's disease in drug-resistant relapse. We also see a relapse rate over 50% in patients given allogeneic BMT for ANLL in second or third remission or early relapse, for ALL in third or subsequent remission or early relapse, and for chronic myelogenous leukemia (CML) in accelerated phase or blast crisis. We have explored two new approaches for improving the anti-tumor activity of our BMT preparative regimens. One involves combining etoposide, a chemotherapeutic agent that has excellent activity against leukemias and lymphomas, has shown synergistic activity with cyclophosphamide in vitro, and can be substantially dose-escalated, with busulfan and cyclophosphamide. The other approach attempts to induce graft-versus-host disease (GVHD), which appears to provide a clinical anti-tumor effect following allogeneic BMT, in recipients of autologous BMT. A syndrome similar to mild GVHD has been reported to occur spontaneously in a small number of patients receiving autologous or syngeneic transplants. GVHD can also be induced in rats undergoing syngeneic BMT by treatment with cyclosporine (CSA).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:New conditioning regimens for high risk marrow transplants. 262 18

A variety of diseases are the result of identifiable cell types entering an abnormal state of development in which they escape existing mechanisms that regulate their growth or other functional activities. A variety of investigators interested in eliminating cells that have undergone malignant transformation have devised immunotherapeutic approaches based on the construction of hybrid molecules composed of highly toxic biological poisons covalently coupled with antibodies specific for membrane antigens expressed selectively by tumor cell targets. This strategy can be further exploited to eliminate any target cell with defined, selectively expressed membrane antigens. The following discussion describes possible uses of such an approach for achieving selective cytotoxicity of lymphocytes with undesirable immunoreactivities, such as those found in autoimmune disease and graft-versus-host disease.
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PMID:Selective elimination of autoreactive lymphocytes with immunotoxins. 264 71

Nine children with poor prognosis neuroblastoma have been treated by continuous infusion of IL-2 and autologous LAK cells, as described previously by West et al. in adult patients. Six patients were in relapse after high-dose chemotherapy and autologous BMT and three presented with primary refractory disease after conventional therapy. Although patients were very young (median age 6 years; average weight 17 kg), infusion of IL-2, cytapheresis and reinjection of LAK cells appeared feasible with the usual and transient complications observed with IL-2. Haematological toxicity, although reversible, was more important than usually described and due to the presence of bone-marrow metastases in 8 of the 9 patients. Life-threatening toxicity was observed in only one of the admission centres and was probably due to the rapid reinjection of a very large number of activated cells. Two patients presenting with very active disease after high-dose chemotherapy and autologous or allogeneic BMT received IL-2 alone, at 120 days and at 90 days after the graft. The reactivation of grade-II GVHD was the major complication in the patient treated after an allograft, whereas no BMT-related toxicity was observed in the patient treated after the autologous BMT. Immunological modifications induced by IL-2 were very different between these patients. As expected, a preferential outgrowth of NK cells with both NK and LAK activity was observed in the patient treated just after the autograft. In contrast, in the patient treated after an allograft and in the 9 patients in relapse, T lymphocytes remained the major mononuclear cell population with a very large excess of CD8+ T cells. All patients progressed after the first induction cycle with the exception of the only patient treated after autologous BMT who reached a very good partial remission with disappearance of the local tumor and bone metastases. Although very preliminary, these data clearly show that the efficacy of IL-2 largely depends on the patient's immunological status with the optimal effect being observed when IL-2 is given in the first few months following an autograft.
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PMID:A phase-II study of adoptive immunotherapy with continuous infusion of interleukin-2 in children with advanced neuroblastoma. A report on 11 cases. 267 Feb 9

Immunotoxins are a new class of antitumor agents consisting of tumor-selective ligands (generally monoclonal antibodies [MoAbs]) linked to highly toxic protein molecules that have been modified to remove their normal tissue-binding domains. These immuno-conjugates combine the potency of the parent toxin with the specificity of the attached ligand. Toxins used in the construction of immunotoxins belong to a group of peptides that catalytically inhibit the elongation step of protein synthesis, and include ricin, abrin, pokeweed antiviral protein, gelonin, Pseudomonas exotoxin A, diptheria toxin, and alpha-sarcin. To synthesize immunotoxins, the normal cell-binding function must be removed by chemical cleavage or modification, or in the case of toxins that have been cloned, genetic engineering used to delete amino acids critical to cell binding. Covalent linkage of toxin to ligand generally involves a disulfide or thioether bond, though recently, recombinant toxin molecules with ligands that are genetically engineered into the protein have been made. The most successful clinical application of immunotoxins has been in the depletion of T cells from allogeneic bone marrow grafts to prevent graft-versus-host disease (GVHD). Clinical trials have been conducted using immunotoxins for the systemic treatment of chronic lymphocytic leukemia (CLL), GVHD, and selected solid tumors. With the possible exception of GVHD, responses have been limited. Obstacles have included rapid systemic clearance, poor delivery to extravascular tumor deposits, and humoral immune responses to the immunotoxin. Research to overcome these problems is in progress and should lead to a better definition of the role of immunotoxins in the therapy of malignancies.
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PMID:Immunotoxins: a clinical review of their use in the treatment of malignancies. 268 83

Previous studies have demonstrated that T cell-depleted (TCD) syngeneic marrow protects against graft-versus-host disease (GVHD) when given along with an allogeneic lymphocyte plus bone marrow (BM) inoculum to lethally irradiated mice. In spite of this anti-GVHD effect, TCD syngeneic marrow is ultimately eliminated by non-TCD allogeneic marrow, permitting complete allogeneic reconstitution. These observations suggested that allogeneic BM might also eliminate host-type leukemic cells in a model in which TCD syngeneic marrow is co-administered to provide protection from GVHD. In the present studies, we describe the establishment of a new model using the EL4 leukemia/lymphoma. Lethally irradiated B10 (H-2b) mice were given a lethal dose of EL4 cells (H-2b) along with syngeneic marrow or a mixture of TCD syngeneic plus non-TCD allogeneic (B10.D2, H-2d) marrow. Non-TCD allogeneic marrow, in contrast to TCD or unmanipulated syngeneic marrow, delayed or prevented mortality from the otherwise lethal EL4 inoculum, without producing clinically apparent GVHD. The anti-leukemic effect of allogeneic marrow alone was not attenuated by the co-administration of TCD syngeneic marrow, and such animals repopulated as completely allogeneic chimeras. Similar anti-leukemic effects of mixed marrow inocula in a haploidentical strain combination, and an anti-leukemic effect against established tumor were also demonstrated. This model may have the potential to increase the safety of clinical bone marrow transplantation across greater HLA disparities, while permitting utilization of the anti-leukemic and alloengraftment-promoting effects of T cells in allogeneic marrow inocula.
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PMID:Graft-versus-leukemia effect using mixed allogeneic bone marrow transplantation. 279 Mar 25

Two children with active metastatic neuroblastoma after high dose chemotherapy and bone marrow transplantation (BMT) received a high dose continuous infusion of interleukin-2 (IL2) 120 days after an autologous BMT for patient 1 and 90 days after an allogeneic non T cell-depleted BMT for patient 2. Usual side effects of IL2 therapy were observed without life-threatening complications or any major hematological toxicity. The reactivation of graft-versus-host disease during IL2 infusion in patient 2 was the major BM-related complication but it improved with IL2 interruption and corticosteroids. IL2 induced a complete remission (9+ months) in patient 1 with the disappearance of bone metastases and local tumor but patient 2 progressed after cessation of therapy. Patient 1 presented with a large excess of circulating NK cells in the period after autologous BMT and IL2 induced a preferential outgrowth of this lymphocyte subset.
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PMID:Systemic interleukin-2 therapy in children with progressive neuroblastoma after high dose chemotherapy and bone marrow transplantation. 279 Mar 27

Autologous bone marrow transplantation (ABMT), which was developed in the past decade, is currently under investigation for the treatment of leukemias, lymphomas, and a few solid tumors. It consists of engrafting a patient, after ablative chemotherapy and/or total-body irradiation (TBI), with marrow taken from the patient at a propitious time in the history of the disease and usually cryopreserved. This technique has two major consequences: ABMT by reducing the length and variability of posttreatment aplasia can be considered a super hematologic support. It allows the use of chemotherapeutic agents and/or TBI at doses that surpass the dose for effecting the threshold of myelotoxicity. Therefore, a greater tumor cell kill can be expected at a reasonably low cost in terms of toxicity. In patients with acute leukemia (AL), however, the contribution of ABMT may go far beyond. In the initial trials (1974-79), the marrow of patients with AL was collected during complete remission and cryopreserved, with the idea of preserving "the remission status." At relapse this marrow was re-infused after high-dose chemotherapy and/or TBI, for achieving another complete remission. The result could be considered a chronologic chimera; the autograft, which had stem cells younger than those of the organism, reproduced, over the course of a few months or years, the evolution of the remission during which it was collected. As predicted, however, all patients who received this treatment eventually relapsed. For a more aggressive technique, some teams gave autografts to patients earlier, during remission, to allow ablative therapy in the consolidation mode; the whole procedure, including the pretransplant cytoreductive regimen, was modeled on that of allografting. Because allogeneic bone marrow transplantation currently offers the best chance of long-term survival but remains severely restricted, by age and availability of an HLA-identical donor, to less than 10% of the patients, ABMT may be considered an alternative source of stem cells to the other patients. In addition, ABMT avoids the risks of graft-versus-host disease with its associated immunosuppression. However, one major impediment to effective ABMT may be the persistence of leukemia cells in the marrow autograft, although the marrow was collected during earlier remission. The recent development of numerous techniques to cleanse the marrow prior to ABMT has considerably increased the possibility of ABMT becoming a major tool in the cure of leukemia. This report reviews the early data and essentially focuses on recent results of ABMT effected in or done in remission with use of cleansed and uncleansed marrow.
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PMID:Autologous bone marrow transplantation in acute leukemia. 294 Apr

A 12-year-old boy with severe combined immunodeficiency who had been kept in a gnotobiotic environment since birth received bone marrow from a histoincompatible sibling in an attempt to reconstitute immunologic function. To prevent graft versus host disease, the donor's marrow was treated in vitro with monoclonal antibody and complement to remove alloreactive T cells. Eighty days after transplantation, the patient had a systemic illness characterized by fever, thrombocytopenia, gastrointestinal pain, and bleeding; he died on the 124th post-transplantation day. Postmortem examination revealed multiple tumor-like B-cell proliferations, recipient in origin, in numerous organs. Epstein-Barr virus (EBV) was isolated from the patient's pharyngeal secretions; EBV nuclear antigen was found in spontaneously transformed peripheral-blood lymphocytes, inflammatory cells from peritoneal fluid, and bone marrow cells; and EBV genomes were discovered in all tumor tissues. The donor's serum showed evidence of past EBV infection. Analysis of cellular immunoglobulin and immunoglobulin gene DNA from the tumors indicated both monoclonal and oligoclonal B-cell proliferations. These findings provide evidence for the evolution of EBV-induced polyclonal activation of B cells to oligoclonal B-cell proliferation and finally to monoclonal B-cell lymphoma.
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PMID:Epstein-Barr virus-associated B-cell proliferations of diverse clonal origins after bone marrow transplantation in a 12-year-old patient with severe combined immunodeficiency. 298 67

The murine 402AX teratocarcinoma is a MHC class I antigen negative tumor of 129 strain origin. Host resistance to the 402AX tumor is genetically controlled. When passed intraperitoneally in genetically resistant mice, the tumor cells are induced to express MHC Class I antigens of the 129 genotype. When passed in genetically susceptible mice, the tumor cells remain MHC class I antigen negative. Earlier studies have demonstrated that resistance to the tumor and regulation of tumor cell MHC class I antigen expression are under the control of the host's immune system. The present studies indicate that splenic Lyt 1-, Lyt 2-, and L3T4-expressing cells regulate tumor cell MHC class I antigen expression, and that these cells require a genetically resistant host environment in which to differentiate. Splenic T cells primed to the 402AX tumor and transferred into genetically susceptible 129 mice give rise to GVHD, suggesting that immunity to the tumor involves reactivity to 129 minor histocompatibility antigens.
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PMID:402AX teratocarcinoma MHC class I antigen expression is regulated in vivo by Lyt 1, Lyt 2, and L3T4 expressing splenic T cells. 309 94

Natural killer lymphocytes can spontaneously kill in vitro a variety of malignant cultured cells. NK cells are present in all normal individuals, and in some species (human, rats) present peculiar morphological features (large granular lymphocytes). They are usually lacking conventional T or B markers, but it appears likely that most NK cells actually are poorly mature cells belonging to the T cell lineage. The physiological control of NK activity is complex. A major role seems to be devoted to the production of interferon. The physiological roles of NK cells are still unknown: they might participate in the control of cell differentiation, in peculiar of hematopoietic precursors and thymocytes; they probably play a role as defense mechanisms during the first days of viral infections; they might be involved in bone-marrow allograft rejection and in acute graft-versus-host disease. However, their actual role in anti-tumor surveillance remains controversial, especially in humans. Nevertheless, NK cells might play some role in the surveillance against leukemias and lymphomas. NK cell defects could participate in the increased occurrence of lymphoproliferative disorders observed in immuno-suppressed patients.
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PMID:[Natural killer lymphocytes. Their role in pathology]. 315 60


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