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)

We have recently demonstrated that high-dose IL-2, when begun on the day of bone marrow transplantation, has a potent protective effect against graft-vs.-host disease mortality, especially when coadministered with T cell-depleted syngeneic bone marrow cells. Because several groups of investigators have demonstrated that lymphokine-activated killer cells can mediate GVHD protection, we hypothesized that the mechanism of protection by IL-2 administration might involve the in vivo activation of natural killer and/or LAK cells. In order to test this hypothesis, we evaluated the effect of IL-2 administration on the number of NK1+ cells and on NK-mediated cytotoxic activity in recipients of GVHD-producing inocula. Furthermore, we evaluated the effects on IL-2-induced GVHD protection of depleting NK cells and LAK precursor cells in vivo with mAb against NK1.1 or antiserum against asialo GM1. The results demonstrate that: (1) The number of NK1+ cells is not increased in spleens of IL-2-treated compared with control recipients of GVHD-producing inocula; (2) NK activity is not increased in IL-2-treated compared with control recipients of GVHD-producing inocula during or immediately following the period of IL-2 administration; (3) depletion of NK cells and LAK precursors from the donor and host influenced the time course of GVHD-related mortality in a complex fashion; and (4) IL-2-induced GVHD protection is largely independent of the activity of an NK or LAK cell population of donor or host origin. IL-2-induced GVHD protection therefore reflects primarily the activity of non-LAK protective cell populations, or it may be a direct inhibitory effect on responding donor cell populations as they encounter host antigen.
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PMID:The mechanism of IL-2-mediated protection against GVHD in mice. II. Protection occurs independently of NK/LAK cells. 153 68

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

Natural suppressor (NS) cell lines were derived from the spleen and thymus of adult mice using procedures previously used to derive NS cells from neonatal spleen. Adult spleen-derived NS cells showed slightly greater suppression of the MLR than neonatal spleen-derived NS cells, and thymus-derived NS cells showed the least suppression. Adult spleen-derived NS cells prevented death from lethal GVHD when administered to sublethally irradiated weanling mice that received an otherwise lethal GVHD provoking inoculum. The stable cell surface phenotype of adult tissue-derived NS cells was similar to that previously described for neonatal and TLI spleen-derived NS cells: strongly positive for Thy 1.2, Ly-5, and asialo-GM1 antigens while negative for Ly-1, Ly-2, L3T4, MAC-1, and surface immunoglobulin.
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PMID:Natural suppressor cells derived from adult spleen and thymus. 252 1

Prompted by our recent finding that lymphokine-activated killer (LAK) cells mediate both veto and natural suppression, we tested the ability of adoptively transferred LAK cells to block two in vivo alloreactions which complicate bone marrow transplantation: resistance to transplanted allogeneic bone marrow cells, and lethal graft-vs-host disease. Adoptive transfer of either donor type B6D2 or recipient-type B6 lymphokine-activated bone marrow cells, cells found to have strong LAK activity, abrogated or inhibited the resistance of irradiated B6 mice to both B6D2 marrow and third party-unrelated C3H marrow as measured by CFU in spleen on day 7. The ability of lymphokine-activated bone marrow cells to abrogate allogeneic resistance was eliminated by C lysis depletion of cells expressing asialo-GM1, NK1.1, and, to a variable degree, Thy-1, but not by depletion of cells expressing Lyt-2, indicating that the responsible cells had a LAK cell phenotype. Similar findings were obtained by using splenic LAK cells generated by 3 to 7 days of culture with rIL-2. Demonstration that allogeneic resistance could be blocked by a cloned LAK cell line provided direct evidence that LAK cells inhibit allogeneic resistance. In addition to inhibiting allogeneic resistance, adoptively transferred recipient-type LAK cells prevented lethal graft-vs-host disease, and permitted long term engraftment of allogeneic marrow. Irradiation prevented LAK cell inhibition of both allogeneic resistance and lethal graft-vs-host disease. These findings suggest that adoptive immunotherapy with LAK cells may prove useful in preventing graft rejection and graft-versus-host disease in human bone marrow transplant recipients.
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PMID:Use of lymphokine-activated killer cells to prevent bone marrow graft rejection and lethal graft-vs-host disease. 266 9

Mice bearing the 'auto-immune' lpr gene develop a lympho-proliferative disease associated with the production of various antibodies. Lethally irradiated recipients were grafted with bone marrow cells (BMC) from syngeneic mice with or without the lpr gene. After 6 months, the survivors were 0/24 and 16/20 for the recipients of lpr and normal BMC respectively. The mortality rate was independent of the presence of T lymphocytes among the BMC. Histological evaluation showed that hepatitis, interstitial pneumonitis, and sclerosis of lymphohaemopoietic organs were the major causes of death for the recipients of lpr BMC. Hepatitis was associated with an increase in the number of liver interstitial cells (LIC) from about 2 X 10(6) up to about 10(7) cells per liver. The LIC associated with the hepatitis were composed of polymorphonuclear leucocytes and large mononuclear leucocytes, showing phenotypic (i.e. Thy.1+, asialo GM1, presence of cytoplasmic granules) and functional (i.e. non-phagocytic and cytolytic) properties of NK cells. The disease can be distinguished both from the spontaneous disease of the lpr mice (by the absence of 'lpr cells' and of anti-DNA antibodies) and from graft versus host disease by the absence of cutaneous and intestinal lesions. It may represent a model of tissue injury mediated by large granular leucocytes.
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PMID:Interstitial pneumonitis and hepatitis after transfer of bone marrow cells bearing the lpr gene to irradiated recipients: a disease due to large granular leucocytes? 332 8

Graft-versus-host disease (GVHD) was induced in irradiated (750 rad) (CBA x C57BL/6)F1 hybrid mice by an intravenous injection of 30 x 10(6) CBA spleen cells and 5 x 10(6) syngeneic F1 bone marrow cells. The GVHD resulted in the death of 80% of recipients within 9 days. However, when radioresistant Asialo-GM1+ cells were depleted from the recipients with a single injection of anti-Asialo-GM1 antibody 2 days before irradiation and transplantation, mortality decreased significantly (to 11%). During the GVHD, anti-host specific cytotoxic T cell (CTL) activity could be shown in vitro in the spleens of mice suffering from the GVHD if suppressor activity was first abolished by in vitro culture procedures. This CTL activity, however, was not detectable in the spleens of anti-ASGM1 antibody pretreated hosts. The results indicate that radioresistant ASGM1+ cells of host origin are necessary for the induction of both anti-host CTL and lethal GVHD.
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PMID:Depletion of asialo-GM1+ cells from the F1 recipient mice prior to irradiation and transfusion of parental spleen cells prevents mortality to acute graft-versus-host disease and induction of anti-host specific cytotoxic T cells. 349 71

Graft-versus-host disease (GVHD) was induced in (CBA X C57BL/6) F1 mice by i.v. injection of 50 X 10(6) parental spleen cells. The GVHD induced an enhanced NK (anti-YAC-1) cytotoxicity during the first 2 weeks after the spleen cell transfusion. This cytotoxic activity was shown to be mediated by asialo GM1-positive, partially Thy-1-positive and nylon-wool (NW) non-adherent cells, thus being classical NK cells. Depletion of NK-cell activity from donor and/or recipient mice with anti-asialo GM1 antibody prior to the spleen cell transfer did not prevent the GVHD as judged by the splenomegaly assay. Also, when NK activity was potentiated with polyinosinic-polycytidylic acid (pIC), no effect on the GVHD was seen. These data suggest that NK cells are not crucial for the development of GVHD in this model.
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PMID:Natural killer (NK) cells and graft-versus-host disease (GVHD): no correlation between the NK cell levels and GVHD in the murine P----F1 model. 397 29

In mice, as in humans, lethal graft-versus-host disease (GVHD) with skin involvement often occurs in immunoincompetent recipients of donor hematopoietic cells in spite of matching at major histocompatibility loci and nonreactivity in mixed lymphocyte culture, if donor and recipient are disparate at several minor histocompatibility loci. In mice, both death and skin disease can be prevented by the use of an antiserum containing antibodies to a cell surface glycolipid, asialo GM1 (ASGM1). Because treatment of only the recipients with anti-asialo GM1 substantially reduces the subsequent proliferation of infused donor lymphoid cells, we infer that anti-asialo GM1 interferes with a host minor-antigen-presenting cell, so that donor lymphocytes fail to see minor host antigens as immunogenic. Of the tissues examined by immunofluorescence microscopy, ASGM1 was found on the epidermal Thy-1+ dendritic cell, on dendritic cells in the thymus, and as has been previously described, on lung and spleen cells. Following the intravenous administration of anti-asialo GM1, only the spleen showed an obvious change, losing approximately 80% of its ASGM1 + cells. Further analysis of spleen cells bearing ASGM1 may better define the phenotype of the inferred minor antigen-presenting cell and lead to a method of improving the outcome of human bone marrow transplantation.
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PMID:Studies addressing the mechanism of anti-asialo GM1 prevention of graft-versus-host disease due to minor histocompatibility antigenic differences. 400 80

Graft-vs-Host disease (GVHD) remains a devastating problem in human bone marrow transplantation (1, 2). Because removal of Thy-bearing cells from the donor inoculum has prevented GVHD in murine models (3, 4), it has been hoped that a similar cell surface antigen or combination of antigens could be found in humans. Unfortunately, treatment of human donor cells with various T cell antisera has not yet been successful in preventing GVHD (5). Encouraging results have been reported in five patients who received bone marrow depleted of T cells by the sequential use of soybean agglutinin and the differential sedimentation of cells forming rosettes with sheep red blood cells (6). Although donor T cells are thought to be necessary for initiating GVHD, the immunopathogenesis of GVHD is still not understood. Because donors and recipients are routinely major histocompatibility complex matched and chosen to be nonreactive in mixed lymphocyte cultures human GVHD is thought to result from minor histocompatibility antigen disparities. Lopez and coworkers (7, 8) found a strong association between the incidence of human GVHD and the pretransplant levels of natural killer (NK) activity of the recipients; when the recipient NK activity was low, GVHD rarely developed. They speculated that the NK cell lineage is serving as an important stimulator-inducer. We therefore examined the in vivo effects of anti-asialo GM1 on a murine model of GVHD based on minor antigen disparity. This antiserum has several immunologic effects, including a profound NK suppression. We found that the mice treated with this antibody have normal survival rates, even though they do develop histologic GVHD in the skin. This finding suggests the possibility of a new prophylactic approach to human GVHD and raises many questions regarding the function of asialo GM1-bearing cells in immune regulation.
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PMID:Prevention of lethal, minor-determinate graft-host disease in mice by the in vivo administration of anti-asialo GM1. 635 91

The nature of the effector cell(s) responsible for the depression of B-cell genesis in the bone marrow of mice undergoing systemic graft-versus-host disease (GVHD) has been examined. Donor C57BL/6 (B6) mice were treated in vivo with either a single injection of anti-asialo GM1 antibody (anti-ASGM1) to eliminate naturally occurring (endogenous) ASGM1+ cells or B6xAF1 (B6AF1) lymphoid cells followed by anti-ASGM1 to eliminate both endogenous and "induced" ASGM1+ cells. Lymphoid cells from donor mice after the elimination of endogenous ASGM1+ cells produced severe GVHD and concomitant depression of B-cell genesis when injected into B6AF1 recipients. In contrast, cells from donors depleted of both the endogenous and inducible ASGM1+ populations did not cause GVHD or depletion of B lineage cells in B6AF1 recipients but did depress B-cell genesis in B6C3F1 mice. The "induced" ASGM1+ cells were Thy 1+, but their elimination did not significantly alter either overall T-cell function or specific cytotoxic T-cell (CTL) reactivity against the sensitizing (B6AF1) strain. The results suggest that the effector cell responsible for the depression of B-cell genesis during systemic GVHD can be induced to express ASGM1, is strain-specific and Thy 1+; but is not a conventional CTL.
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PMID:A donor-derived asialo-GM1+ cell induces depression of B-cell genesis during systemic graft-versus-host disease. 794 52


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