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)

Syngeneic graft-versus-host disease (SGVHD) is a T cell-mediated autoimmune disease occurring postsyngeneic bone marrow transplantation and the administration of the potent immunosuppressive agent, cyclosporine A. Paradoxically, cyclosporine A disrupts the immunologic homeostasis governing self-tolerance. Our studies using an adoptive transfer model attempted to identify effector mechanisms associated with the autoimmune disease. Both CD4+ and CD8+ splenic T cells isolated from autoimmune donors were required for the adoptive transfer of active disease into lethally irradiated secondary recipients reconstituted with normal bone marrow. Doses of more than 5 x 10(6) of nylon wool depleted splenocytes from autoimmune donors effectively transferred disease into lethally irradiated secondary recipients. Splenocytes that are T cell depleted or CD4(+)-enriched cells did not elicit disease upon adoptive transfer. Nylon wool fractionated CD8+ splenocytes also failed to adoptively transfer disease unless high doses (greater than or equal to 30 x 10(6)) were used. The disease transferred with the CD8+ subset presented as acute type SGVHD and was self-limiting. The recombination of the individually isolated T cell subsets not only restored but also enhanced immune reactivity upon adoptive transfer. Moreover, use of the recombined subsets resulted in progressive disease with the development of chronic type SGVHD. The titration of each subset to the other suggested that a minimal number of CD4+ T cells was required to potentiate the CD8+ autoreactive cells in vivo. Further analysis of the helper cell involved demonstrated that it had a CD4+ CD45r- phenotype, characteristic of an amplifying helper cell population. Administration of IL-2 did not substitute for CD4+ Th cells but yet amplified the activity of unfractionated cells or recombined subsets implicating the role of other factors in the pathogenesis of SGVHD. Delineation of the effector mechanisms involved in SGVHD is critical in determining the underlying events that trigger either the production of autoreactive cells or the perturbation of the regulation of these autoreactive cells, culminating in autoimmunity.
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PMID:Effector mechanisms in cyclosporine A-induced syngeneic graft-versus-host disease. Role of CD4+ and CD8+ T lymphocyte subsets. 197 85

We have investigated the effects of graft-versus-host disease on T cell differentiation in the murine thymus. We previously reported that GVH-induced thymic dysplasia results in a T cell immunodeficiency associated with a lack of IL-2 production. This deficiency in IL-2 production may be the result of a reduction in the number of L3T4+Lyt-2- IL-2-producing cells or of a functional defect in this population. To test these two alternatives, flow cytometry analysis of L3T4 and Lyt-2 antigen expression on thymocytes along with immunofluorescence microscopy were employed to assess T cell phenotypes in thymuses of GVH mice. GVH reactions were induced by injecting 40 x 10(6) C57BL/6 (B6) or A strain lymphoid cells into C57BL/6xAF1 (B6AF1) mice. Thymocyte populations were quantitated on different days after GVH induction. In the normal thymus, the ratio of L3T4/Lyt-2 single positive cells was greater than 2:1. In contrast, such a ratio was less than 1:1 in the atrophic GVH thymus, owing to a selective reduction in the number of L3T4+Lyt-2- cells. Following cortisone treatment the ratio of L3T4/Lyt-2 single positive thymocytes in normal F1 mice was approximately 3:1, whereas in GVH animals this ratio was reversed (1:2). This reversal was due to a selective reduction in the absolute numbers of L3T4+Lyt-2- cells. In adrenalectomized GVH animals, thymic cortical atrophy was prevented and normal ratios of L3T4/Lyt-2 single positive cells were observed. However, when these animals were treated with cortisone, the L3+T4/Lyt-2- population was more sensitive than was the L3T4- Lyt2+ population, thereby resulting in a 1:2 L3T4/Lyt-2 ratio. These results demonstrate that single positive L3T4 cells are present in the murine GVH thymus, yet they have not acquired cortisone resistance, a trait normally attributed to this mature thymic subset. It appears that the GVH dysplastic thymus can support the differentiation of L3T4+Lyt-2- cells--however, such a thymus is unable to confer cortisone resistance upon this population. Consequently, these cells appear to be eliminated when exposed to corticosteroids in peripheral lymphoid tissue.
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PMID:T cell subsets in the thymus of graft-versus-host immunosuppressed mice. Sensitivity of the L3T4+Lyt-2- subset to cortisone. 198 97

We have used limiting dilution culture methods to determine the frequency of mitogen-responsive T cells in peripheral blood of patients after bone marrow autotransplantation, and have compared their responsiveness to that of allotransplant recipients and normal controls. Autotransplant patients were found to have low responder cell frequencies in tests for lymphokine-secreting helper function, and for IL-2 dependent proliferator and cytotoxic function. Multiple regression analysis showed that function was lower in autotransplant patients than in allorecipients, and lower in male patients for all three functional assays. Patients with clinically significant infection tended to have lower proliferative function in both transplant groups and lower cytotoxic function in the allotransplant population. Graft-versus-host disease was associated with lower T-cell function, but was present only in the allotransplant group; therefore, it cannot account for the even lower levels of function observed in the autotransplant population. Because we observe deficits in T-cell regeneration in autotransplant recipients that are even more severe than in allorecipients, we postulate that cellular immunodeficiency after bone marrow transplantation may reflect limitations in thymic-dependent repopulation rather than an effect of genetic disparity between host and donor (eg, clinical or subclinical graft-versus-host).
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PMID:Clonal analysis of T-cell deficiencies in autotransplant recipients. 201 8

We have recently demonstrated that high-dose IL-2 administered for a short period (2.5 days) beginning on the day of bone marrow transplantation mediates a marked protective effect against GVHD in mice, while preserving the ability to achieve alloengraftment (1). This protective effect is augmented by administration of T cell-depleted (TCD) syngeneic marrow, and is dependent upon early administration of IL-2 (1). The graft-vs-tumor effect against the EL4 leukemia/lymphoma is not diminished in animals protected from GVHD by IL-2 (2). In an attempt to determine whether or not IL-2-activated host-type cells might be responsible for GVHD protection, we have now performed adoptive transfer studies. The results failed to provide evidence that treatment of lethally irradiated mice with IL-2 activates protective host-derived or syngeneic marrow-derived cell populations which can be adoptively transferred to lethally irradiated secondary recipients receiving allogeneic GVHD-producing inocula. Likewise, treatment of lethally irradiated mice with a complete 2.5-day course of IL-2 prior to administration of allogeneic inocula did not lead to GVHD protection. These results suggest that either IL-2 directly inhibits the GVH reactivity of allogeneic GVH-reactive cells, or that GVH reactivity is attenuated by IL-2 during the period of interaction of donor- and host-type cells.
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PMID:Mechanism of the anti-GVHD effect of IL-2. I. Protective host-type cell populations are not induced by IL-2 treatment alone. 204 82

The development of methods of avoiding graft-versus-host disease (GVHD) while retaining the alloengraftment-promoting and anti-leukemic effects of allogeneic T cells is a major goal of research in bone marrow transplantation (BMT). We have recently obtained evidence suggesting that natural suppressor (NS) cells derived from T cell-depleted (TCD) syngeneic marrow can protect against GVHD while permitting alloengraftment. We have now attempted to enrich and then propagate NS cells in vitro, with the goal of obtaining an enhanced anti-GVHD effect by adoptive transfer in vivo. Two long-term cell lines were generated culturing BMC depleted of Mac1-positive cells and of Mac1-positive plus Thy1-positive cells in high concentrations of IL-2. Both cell lines showed anti-GVHD effects when administered along with a GVHD-producing inoculum, while permitting complete allogeneic reconstitution. A clone derived from Mac1-depleted BMC protected completely against a more chronic pattern of GVHD. These cell lines demonstrated suppressive activity in vitro, cytolytic activity against a broad range of natural killer (NK)-sensitive and NK-resistant targets, and a novel cell surface phenotype, with characteristics of both alpha beta-TcR-bearing T cells and of NK cells. In some respects, these cells resemble LAK cells and differ from fresh NS cells, and from the cloned NS cells derived from spleens of total lymphoid irradiation (TLI)-treated mice and neonatal mice. To our knowledge, this is the first detailed phenotypic analysis of cell lines with in vivo anti-GVHD activity. If applicability can be demonstrated in large animal models, the ability to use bone marrow as a source of such protective cell lines might also have potential utility in clinical BMT.
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PMID:In vitro and in vivo analysis of bone marrow-derived CD3+, CD4-, CD8-, NK1.1+ cell lines. 214 39

Injection of parental C57BL/10 spleen cells into unirradiated immune-competent (B10 x B10.BR)F1 hosts has been demonstrated to produce a graft-vs.-host-induced immune deficiency in T cell-mediated functions, including mitogen or alloantigen stimulated proliferation or cytotoxic T cell generation. The production of T cell-derived lymphokines affecting hematopoiesis was also altered during GVH. During the first two weeks of GVH, IL-3 and particularly GM-CSF were produced spontaneously; in subsequent weeks, the spontaneous production dropped to normal or subnormal levels. CSF content in concanavalin A-stimulated splenic supernatants was reduced at weeks 1-2, and declined to less than 5% of normal levels by 3-4 weeks of GVH. This decline in CSF content was correlated with a decrease in immune function as assessed by concanavalin A-stimulated IL-2 production and by generation of cytotoxic T lymphocytes. Concurrent with the recovery of immune function during GVH weeks 8-15, mitogen-stimulated production of CSF returned to normal levels. In addition to the decrease in CSF production identified in acute suppressive GVH, CSF content in concanavalin A-stimulated splenic supernatants was also decreased in chronic stimulatory GVH, generated in the strain combination (B6 x B6bm1)F1----(B6bm1 x B6bm12)F1. This decrease in CSF production correlated with a decrease in self-restricted T helper cell function. Finally, a decrease in both immune function and CSF production capacity was observed in the acute GVH following allogeneic (minor histocompatibility loci) bone marrow transplantation into irradiated hosts.
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PMID:Alterations in T cell-derived colony-stimulating factors associated with GVH-induced immune deficiency. 218 11

A murine IgG1 antibody specific for the IL-2-binding site on the human lymphocyte IL-2 receptor beta chain (CD25) was evaluated in 11 patients who developed acute graft-versus-host disease following allogeneic marrow transplantation. All patients had received cyclosporine and methotrexate for prophylaxis of GVHD, either alone (4 cases), or in combination with antithymocyte globulin (4 cases) or with prednisone (3 cases). Patients had developed GVHD at 7-53 days (median 12) after transplantation and had failed treatment with corticosteroids for 3-44 days (median 19). Residual GVHD was of grade II severity in 4 patients, grade III in 5 patients, and grade IV in 2 patients. Sequential patients received monoclonal antibody in escalating doses from 0.1 mg/kg/day to 1.0 mg/kg/day for 7 days. Side effects were fever, respiratory distress, hypertension, hypotension, and chills occurring in 11 of 72 (14%) antibody infusions. Trough antibody levels greater than 6 micrograms/ml were achieved in patients treated with 0.5 or 1.0 mg/kg/day. Four of eight evaluable patients had an IgM antibody response, and one had an IgG response to the murine immunoglobulin. Clinical response of GVHD was evaluated in 10 patients who received the entire course of the antibody treatment. Among 7 patients treated within 40 days from transplantation, one patient had a complete response in the skin as the only involved organ, and 3 patients had a partial response, 2 in the skin and one in the gastrointestinal tract. No responses were achieved with liver disease at anytime or in any organ in patients treated beyond 40 days after transplantation. Since administration of this antibody was well tolerated and some efficacy was observed in patients with acute GVHD treated early after transplantation, there is a rationale for testing this antibody as an agent for prophylaxis of GVHD.
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PMID:A phase I-II study evaluating the murine anti-IL-2 receptor antibody 2A3 for treatment of acute graft-versus-host disease. 236 50

The ability of alloimmune spleen cells expanded in mixed leukocyte culture (MLC) and cloned cytotoxic T lymphocytes (CTL) to kill H-2-compatible leukemia in vivo was evaluated. In comparison with fresh alloimmune spleen cells, MLC-expanded cells had a significantly higher frequency of CTL reactive against leukemia targets in vitro. However, the reactivity of MLC-expanded cells against first-passage spontaneous AKR (H-2k) leukemia in vivo was significantly less than when an equivalent number of fresh alloimmune spleen cells was injected. Comparable antileukemia reactivity was observed in vivo only when the inoculum of MLC-expanded cells was 2-3-fold higher than that of fresh spleen cells. This relative ineffectiveness was attributed to the altered migration pattern of cultured cells in vivo. IL-2-dependent cloned CTL, specific for a normal lymphocyte antigen (Qa-1b) also present on leukemia cells, were derived from MLC-expanded cultures and tested in vivo. For cloned CTL, as with MLC-expanded cells, eradication of AKR leukemia in vivo was associated with the tissue distribution pattern of the injected effector cells. That is, an effective antileukemia reaction was achieved only in tissues in which effector and target proximity was maintained. Qa-1b-specific cloned CTL did not interfere with engraftment of autologous or allogeneic bone marrow in lethally irradiated host mice, nor did they cause any clinically evident graft-versus-host disease. These findings suggest that cloned CTL specific for a normal cell surface antigen with limited host tissue distribution, but present on tumor cells, could be used for adoptive immunotherapy, provided CTL and tumor cell proximity can be attained.
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PMID:Reactivity of in-vitro-expanded alloimmune cytotoxic T lymphocytes and Qa-1-specific cytotoxic T lymphocytes against AKR leukemia in vivo. 241 69

Epa-1 is a tissue-restricted, non-major histocompatibility (MHC) antigen that may be responsible for the extreme sensitivity of skin to allograft rejection and graft-versus-host disease (GVHD), especially with MHC-compatible donors and recipients. To confirm that Epa-1 serves as a target in allograft rejection and GVHD, we isolated Epa-1-specific cytotoxic T lymphocyte (CTL) clones completely in vivo from sponge-matrix allografts and from lymph nodes draining rejecting skin allografts. These clones induced GVHD-like skin lesions in antigen-specific, MHC-restricted fashion following intradermal inoculation into appropriate hosts. The in vivo-derived clones are conventional CTL since they are IL-2-dependent and express the Thy-1.2+, Lyt-1-, Lyt-2+, L3T4- phenotype. The results of this study also are pertinent to the controversy over which T-cell subset actually mediates allograft immunity, since the intragraft isolation and subsequent cloning of conventional CTL that induce necrotizing skin lesions are direct evidence that CTL are the proximal mediators of allograft rejection.
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PMID:In vitro and in vivo cytotoxicity of T cells cloned from rejecting allografts. 242 46

Injection of B10.D2 cells into irradiated H-2d compatible (DBA/2xB10.D2)F1 recipients provokes a lethal GVH that can be abrogated by donor preimmunization against host-specific DBA/2 non-H-2 antigens. To study the possible relationship between the observed protection and restoration of immune responsiveness, we compared spleen cellularity, selected T and B cell functions, and NK activity in GVH and protected mice during the 1st month after grafting. Normal and isografted mice served as controls. GVH was found to be characterized by an early stimulation phase associated with splenomegaly and increased percentages (but not numbers) of Lyt-2+ and L3T4+ cells, followed by profound aplasia and abrogation of IL-2 production. Response to a B cell mitogen (LPS) is depressed, and cells from GVH mice exert a strong suppressive effect on the LPS and PHA responsiveness of normal cells. Suppression appears to be mediated by a radioresistant, nylon nonadherent, asialo GM1 negative cell expressing a low level of Thy-1 antigen. In contrast, protection correlates with progressive restoration of spleen cellularity and LPS responsiveness, with decreased but clearly detectable IL-2 production, and transient nonspecific suppressor activity. The immune status of protected mice resembles that of isografted controls. No correlation was found between mortality (or protection) and either PHA responsiveness, which remained depressed in all grafted mice throughout the observation period, or NK activity, which was strongly depressed in both GVH and protected mice. In conclusion, protection correlates with the disappearance of nonspecific suppressor cells and the restoration of cellularity and certain nonspecific immune functions. Donor immunization against host-specific non-H-2 antigens, which protects against mortality, also protects against GVH-associated immune deficiency.
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PMID:Lethal graft-versus-host reaction against non-H-2 antigens. I. Prevention of GVH-associated immunodeficiency by preimmunizing the donor against host-specific non-H-2 antigens. 252 8


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