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 ability to define subpopulations of immunologically competent lymphocytes has permitted an enhanced understanding of the interaction between functionally distinct components of the immune system. T cells can provide help in antibody formation or they may suppress antibody production. Abnormal immunoregulatory mechanisms have been demonstrated in the hyperimmunoglobulin E-recurrent infection syndrome. This disorder is associated with a marked elevation of IgE and specific elevations of IgE antibodies directed toward staphylococcal antigens. Abnormal T cell regulation of immune responses has been demonstrated. Graft-versus-host disease (GVHD) occurs in an immunodeficient patient who has received an infusion of immunocompetent cells. The diagnosis of graft-versus-host (GVH) reaction may be complicated by the protean manifestations of the disorder. The acute form, consisting of a maculopapular rash, fever, and diarrhea, may be confused with acute infection or drug reaction. Chronic GVHD has been incorrectly diagnosed as histiocytosis X, acrodermatitis enteropathica, or scleroderma. Utilizing chromosome markers and/or identification of histocompatibility antigens, the presence of circulating lymphocytes from donor immunocompetent cells (blood transfusion, maternal source) can be documented. The development of sensitive technics for identifying cells can establish a precise diagnosis. Certain immunodeficiency disorders can be identified by biochemical means. Biotin-dependent multiple carboxylase enzyme deficiency is associated with a chronic dermatitis, alopecia, ataxia, and secondary infection of the skin with Candida. The disorder responds promptly to the administration of biotin with correction of dermatologic, neurologic, and immunologic abnormalities.
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PMID:New insight into the causes of immunodeficiency disorders. 638 1

Enzyme replacement therapy was successfully accomplished in beta-Glu-deficient C3H/HeJ mice after transplantation of BM cells obtained from normal BALB/c donors. Marrow recipients were prepared for transplantation by fractionated TLI. Enzyme activity increased from 20.5 +/- 7.0 nmol/mg of protein per hour to 180 +/- 30.2 in the liver (p less than 0.001) and from 8.2 +/- 2.0 to 17.5 +/- 5.0 nmol/ml/hr in the plasma (p less than 0.05) at 50 days after marrow infusion. Normal enzyme activity was maintained in treated mice for at least 100 days after marrow transplantation, as documented by repeated liver biopsies and examination of plasma samples. The marrow donors and the recipients were fully histoincompatible. Both immunologic rejection of the marrow allograft and GVHD were prevented by the prior conditioning of the recipients with TLI, resulting in bilateral transplantation tolerance of host vs. graft and graft vs. host. The data suggest that allogeneic BM transplantation may provide a possible therapeutic approach for certain enzyme deficiency syndromes.
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PMID:Long-term enzyme replacement therapy in beta-glucuronidase--deficient mice by allogeneic bone marrow transplantation. 704 73

Development of partial conditioning strategies to achieve reliable engraftment of allogeneic bone marrow with minimum recipient morbidity could extend the therapeutic application of bone marrow transplantation (BMT) to enzyme deficiency states, hemoglobinopathies, autoimmune diseases, and the induction of tolerance for solid organ and cellular allografts. In this study we describe a nonmyeloablative rat BMT model and examine the effect of clinically available immunosuppressants on the minimum amount of total body irradiation (TBI) required for allogeneic engraftment. Donor ACI marrow was depleted of T cells using immunomagnetic beads and transplanted to major histocompatibility complex- and minor antigen-mismatched Wistar Furth (WF) rats (ACI --> WF) conditioned with varying doses of TBI. Recipients conditioned with TBI alone required myeloablation with 1000 cGy for reliable allogeneic marrow engraftment. Administration to WF recipients of a single dose of anti-lymphocyte serum (ALS) 5 days prior to BMT together with a limited course of tacrolimus (1 mg/kg/day) resulted in engraftment of ACI bone marrow at only 500 cGy TBI. ACI --> WF recipients were stable mixed chimeras (mean donor chimerism 49% at 330 days post-BMT). Chimerism was multilineage. All recipient animals were free of graft-versus-host disease. These results suggest that a nonmyeloablative conditioning strategy based on low-dose TBI and a limited course of tacrolimus plus ALS can produce long-term mixed multilineage chimerism.
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PMID:A partial conditioning strategy for achieving mixed chimerism in the rat: tacrolimus and anti-lymphocyte serum substantially reduce the minimum radiation dose for engraftment. 972 27

Bone marrow transplantation (BMT) has the potential to treat hemoglobinopathies (sickle cell and thalassemia) autoimmunity (diabetes, lupus, multiple sclerosis, rheumatoid arthritis, Crohn's colitis) and enzyme deficiency states. Graft versus host disease (GVHD) is a major complication and limitation to the therapeutic application of BMT. There have been many clinical trials and experimental animal models that have attempted to control GVHD through the engineering of the donor bone marrow cells (BMC). Historically, several methods have demonstrated effectiveness in controlling GVHD; however they were also associated with a marked increase in the rate of graft failure. Highly purified hematopoietic stem cells (HSC) engraft quite readily in genetically-matched recipients while they do not engraft as easily in MHC-disparate recipients. The numbers of HSC must be increased 100-200 fold in order to overcome the allogeneic barrier. We were the first to phenotypically and to functionally characterize a novel cell in the bone marrow that enables engraftment of highly purified HSC in allogeneic recipients. The discovery of graft facilitating cell populations has resulted in the restoration of the engraftment-potential of purified HSC between genetically-disparate individuals. The addition of facilitating cells (FC) to T cell-depleted BMC grafts results in allogeneic engraftment without GVHD or graft failure. New strategies of BMC engineering that retain FC and HSC but avoid GVHD have allowed successful engraftment in mismatched and older recipients. These techniques have expanded the therapeutic potential of BMT to virtually every candidate as well as to non-malignant diseases in which the morbidity associated with conventional BMT could not be accepted. This article reviews the transition of the FC technology from bench to bedside and discuss the potentially broad-reaching applications of BMT and mixed chimerism.
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PMID:Bone marrow cell graft engineering: from bench to bedside. 1134 54

Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeutic tool for the treatment of an otherwise incurable broad spectrum of malignant and non-malignant diseases. Until recently, BMT was used primarily to replace a malignant, genetically abnormal or deficient immunohematopoietic compartment and therefore, highly toxic myeloablative regimens were considered mandatory for more effective eradication of all undesirable host-derived hematopoietic cells, including stem cells and their progeny. Our preclinical and ongoing clinical studies indicated that much more effective eradication of host immunohematopoietic system cells can be mediated by donor lymphocytes in the process of adoptive allogeneic cell therapy following BMT. Thus, eradication of all malignant cells, especially in patients with CML and, to a lesser extent, in patients with other hematologic malignancies can be accomplished despite complete resistance of puch tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft-versus-malignancy effects might be used as a tool for eradication of otherwise resistant tumor cells of host origin. We speculated that the therapeutic benefit of BMT may be improved by using safer conditioning for engraftment of donor stem cells induce host-versus-graft unresponsiveness to enable engraftment of donor lymphocytes for subsequent induction of graft-versus-malignancy effects, or even graft-versus-autoimmunity and graft-versus-genetically abnormal cells. In other words, focusing on more selective and smarter rather than stronger modalities. Effective BMT procedures may be accomplished without lethal conditioning of the host, using a new, well-tolerated and user-friendly non-myeloablative regimen, thus eliminating or minimizing immediate and late procedure-related toxicity and mortality. It appears that initial induction of graft tolerance, mediated by engraftment of donor stem cells, leads to durable engraftment of immunocompetent donor lymphocytes, which may be necessary for induction of effective biologic warfare against host-type immunohematopoietic cells. Consequently, stem-cell therapy following induction of transplantation tolerance by selective elimination of alloreactive donor lymphocytes may represent the treatment of choice for a wide range of otherwise incurable diseases, including cancer (hematologic malignancies and certain metastatic solid tumors), genetic disorders (hemoglobinopathies and enzyme deficiency disorders), diseases caused by self-reactive lymphocytes (autoimmune diseases such as multiple sclerosis, rheumatoid arthritis) to mention just a few. Using reduced intensity conditioning, non-myeloablative stem cell transplantation (NST) can be accomplished with no major procedure-related toxicity or mortality. Thus, NST offers the feasibility of safe stem cell transplantation and cell-mediated procedures for a large and constantly growing spectrum of clinical indications for all patients in need without lower or upper age limit. Future strategies currently under investigation include developing new approaches for control of alloreactivity of host-versus-graft and graft-versus host reactivity reactions and developing better approaches for maximizing the capacity of donor lymphocytes to eliminate cancer cells more selectively, while avoiding or minimizing GVHD for safer and more effective treatment of patients in need of BMT.
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PMID:Reduced-intensity conditioning for the treatment of malignant and life-threatening non-malignant disorders. 1538 19