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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)

Graft-versus-host disease (GVHD), a serious complication of allogeneic bone marrow transplantation (BMT), can be prevented by in vitro depletion of T cells from the bone marrow (BM) prior to transplantation. The purpose of this study was to assess the role of BMT cells in the reconstitution of various immune functions following BMT across minor histocompatibility barriers. Lethally irradiated CBA/J (H-2k) mice were grafted with either 10(7) unseparated or T-cell-depleted BM cells from B10.BR (H-2k, minor-histoincompatible) mice. Blood counts, BM colonies in agar, and various immune functions of spleen cells from the recipient mice were tested 2-12 weeks post-BMT and compared with those of normal donors. The following observations were made: (A) Peripheral blood lymphocyte counts decreased to 30% of normal 2 weeks post-BMT with almost normal recovery at 8 weeks. (B) The percentage of Thy1.2+ splenocytes reached normal levels at 8 weeks post-BMT. (C) The number of BM colonies (GM-CFU) was reduced to 10% at 2 weeks and fully recovered at 12 weeks. (D) Proliferative response to the B-cell mitogen LPS was fully reconstituted after 4 weeks; however, anti-SRBC PFC (following Mishell-Dutton cultures) was restored 50% at 8-12 weeks. (E) Reconstitution of T cell functions including proliferative responses to concanavalin A, phytohemagglutinin, and allogeneic leukocytes, and allocytotoxicity, did not exceed 50% even 12 weeks post-BMT. Overall, depletion of T cells from donor BM allografts incompatible at minor histocompatibility loci, did not seem to significantly alter the rate of immunohematopoietic reconstitution in the lethally irradiated BM recipients.
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PMID:Bone marrow transplantation with T-cell-depleted grafts. II. Reconstitution of immunohemopoietic functions in lethally irradiated mice transplanted with unseparated or T-cell-depleted bone marrow grafts disparate at minor histocompatibility antigens. 295 82

Natural suppressor (NS) cells are capable of suppressing immunological responses in a nonspecific manner. Previously, we have described NS cells in the spleens of mice undergoing chronic graft-versus-host disease (GVHD) and also in normal B10.D2 bone marrow (BM). NS cells obtained from these environments appear dependent upon lymphokines for their ability to manifest suppression. In this report, with anti-IFN-gamma antibody, we show that IFN-gamma is necessary for NS cell activation. Anti-IFN-gamma antibody is able to remove the ability of NS cells to suppress a concanavalin A (Con A) proliferation assay. Also, anti-IFN-gamma antibody removes the ability of rIL-2, lectin-free Con A supernate (CAS), and recombinant IFN-gamma (rIFN-gamma) to enhance NS suppression of lipopolysaccharide response. By these criteria, IFN-gamma is required for NS cell activation, and rIL-2 may act indirectly by its ability to stimulate IFN-gamma synthesis. These results are discussed in the context of the immuno-suppression seen in human BM transplantation.
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PMID:Evidence that IFN-gamma is responsible for natural suppressor activity in GVHD spleen and normal bone marrow. 296 35

Graft-versus-host disease (GVHD) was produced by injecting lymphoid cells from B10.D2 mice into BALB/C mice. Both are H-2-identical but differ only at multiple minor H loci. The expression and localization of MHC class II antigens on the bile duct epithelium was examined using an immunoelectron microscopical method. All GVHD mice developed bile duct lesions of chronic nonsuppurative cholangitis and expressed MHC class II antigens on their bile duct epithelium, while none of the control mice, which injected with the same number of syngeneic lymphocytes, developed bile duct lesions or expressed the antigens. The antigenic expression was characteristically localized on the basolateral surface of the bile duct epithelium but not on the apical surface. Furthermore, the expression varied markedly in its intensity and distribution within the same liver and even within a single bile duct. The infiltration of Lyt-1-positive helper/inducer lymphocytes in the duct epithelial layer apparent by electron microscopy was predominant to a much degree than that of Lyt-2-positive cytotoxic/suppressor lymphocytes and non-lymphocytic cells. The immunological mechanisms involving helper/inducer T cells in association with MHC class II antigens on bile duct epithelium may be important in the induction and progression of the bile duct lesions apparent in the present GVHD model.
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PMID:Histological changes of bile duct in experimental graft-versus-disease across minor histocompatibility barriers. III. Immunoelectron microscopic observations. 296 70

Resting PEC and fractions of spleen cells adherent to nylon wool (NASC) or polystyrene (PASC) from A/Ph mice evoke a weak regional GVHR or no systemic GVHR in (B10 X A/Ph)F1 hybrids. Blockage of macrophages in vivo by silica or silica gels or removal in vitro of cells phagocytosing iron particles did not change GVH reactivity of A/Ph spleen cells. Addition of PEC or NASC from A/Ph mice to the A/Ph spleen cell suspension somewhat suppressed regional GVHR but enhanced systemic GVHR. Addition of PASC from A/Ph mice, conversely, enhanced regional GVHR and suppressed systemic GVHR. Repeated administration of silica and silica gel to the recipients suppressed regional GVHR; a single dose of silica was most effective at suppression when given one day before the cells. Systemic GVHR was not influenced by this treatment of the recipients. The results indicate that macrophages do not directly induce a GVHR, but they serve as important targets in regional GVHR. In regional and systemic GVHR macrophages perform regulatory functions. Macrophages of donor origin may modify both types of GVHR significantly, depending on the source and type of macrophages and the treatment of donors.
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PMID:A study of the role of macrophages in the graft-versus-host reaction. 298 74

Lethally irradiated F1 mice, heterozygous at the hematopoietic histocompatibility locus Hh-1, which is linked with H-2Db, reject bone marrow grafts from H-2b parents. This hybrid resistance (HR) is reduced by prior injection of H-2b parental spleen cells. Because injection of parental spleen cells produces a profound suppression of F1 immune functions, we investigated whether parental-induced abrogation of HR was due to graft-vs-host-induced immune deficiency (GVHID). HR was assessed by quantifying engraftment of H-2b bone marrow in F1 mice with the use of splenic [125I]IUdR uptake; GVHID, by the ability of F1 spleen cells to generate cytotoxic T lymphocytes (CTL) in vitro. We observed a correlation in the time course and spleen cell dose dependence between loss of HR and GVHID. Both GVHID and loss of HR were dependent on injection of parental T cells; nude or T-depleted spleen cells were ineffective. The injection of B10 recombinant congenic spleens into (B10 X B10.A)F1 mice, before grafting with B10 marrow, demonstrated that only those disparities in major histocompatibility antigens that generated GVH would result in loss of HR. Thus, spleens from (B10 X B10.A(2R]F1 mice (Class I disparity only) did not induce GVHID or affect HR, whereas (B10 X B10.A(5R))F1 spleens (Class I and II disparity) abrogated CTL generation and HR completely. GVHID produced by a class II only disparity, as in (B10 X B10.A(5R))F1 spleens injected into (B6bm12 X B10.A(5R))F1 mice, was also sufficient to markedly reduce HR to B10 bone marrow. This evidence that GVHID can modulate hematopoietic graft rejection may be relevant to the mechanisms of natural resistance to marrow grafts in man.
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PMID:Abrogation of hybrid resistance to bone marrow engraftment by graft-vs-host-induced immune deficiency. 309 24

Highly purified populations of L3T4+ and Lyt-2+ T cell subsets were compared for their capacity to cause lethal GVHD in six different H-2-compatible, multiple minor histocompatibility antigen-different murine strain combinations. In four of these combinations (C3H.SW----B6, DBA/2----B10.D2, B10.BR----CBA, and B10.S----SJL), lethal GVHD appeared to be caused almost entirely by Lyt-2+ cells; the injection of L3T4+ cells resulted in low mortality even when these cells were presensitized to the recipient antigens. In the remaining two combinations (B10.D2----DBA/2 and B10.D2----BALB/c), L3T4+ T cells were able to cause a high incidence of GVHD and were more potent than the Lyt-2+ cells. The implications of these findings are discussed.
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PMID:Variable capacity of L3T4+ T cells to cause lethal graft-versus-host disease across minor histocompatibility barriers in mice. 310 46

Immunosuppression is a well-characterized consequence of chronic graft-versus-host disease (GVHD). We have previously shown that interferon (IFN) is produced in high levels during acute GVHD. Our objective in this study was to determine if IFN, as a cytokine with known immunosuppressive qualities, could be detected in mice experiencing chronic GVHD-induced immunosuppression. Two different experimental models were used to induce chronic GVHD. The first model involved the injection of parental strain spleen cells into adult F1 hybrids (AJ----B6AF1), while the second model utilized GVHD induced across minor histocompatibility barriers (B10.D2----BALB/c). Results indicated that significant levels of serum IFN-alpha/beta are present in mice undergoing chronic GVHD. Spleen cells from chronic GVHD mice were also shown to produce significant levels of IFN-alpha/beta upon in vitro culture in medium only. This IFN-alpha/beta production was greatly increased when GVHD spleen cells were cultured with either concanavalin A (Con A) or IL-2. In contrast, IFN-gamma production was undetectable in these Con A- or IL-2-containing cultures. Additionally, these same spleen cells which produced high levels of IFN-alpha/beta were immunosuppressed as measured by mitogen-induced cell proliferation. These results suggest that IFN-gamma production is defective in GVHD spleen cells, and that the presence of high IFN-alpha/beta production by GVHD mice may contribute to the immunosuppression associated with chronic GVHD.
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PMID:Enhanced interferon-alpha/beta (IFN-alpha/beta) and defective IFN-gamma production in chronic graft versus host disease: a potential mechanism for immunosuppression. 311 28

Irradiated CBA/J mice transplanted with H-2 compatible, minor histocompatibility disparate B10.BR bone marrow develop graft-versus-host disease (GVHD) if mature T lymphocytes are added to the marrow inoculum. In the setting of mild GVHD (receiving 10(4) or 10(5) T cells), by phenotypic analysis, lymphoid reconstitution occurs normally within 4 to 6 wk but there is a profound deficiency in the ability of splenic lymphocytes to respond to polyclonal activators such as LPS and Con A. This unresponsiveness is attributable to active suppression mediated by cells that express Thy-1 and can be removed with leucine methyl ester treatment. Thus, splenocytes from mice with GVHD suppress responses of normal T and B lymphocytes. Moreover, depletion of these suppressor cells restores normal function to splenocytes from mice with GVHD, and B cells isolated from these mice respond normally to T-dependent and -independent stimulation. Finally, IFN-gamma plays an important role in this suppression, because a neutralizing anti-IFN-gamma mAb significantly removes suppression of normal cells and restores functional responses of lymphocytes from mice with GVHD. These results provide insights into the mechanisms of immunodeficiency associated with GVHD, and suggest novel strategies for possible therapies for this disorder.
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PMID:Immunodeficiency in graft-versus-host disease. I. Mechanism of immune suppression. 312 5

We have shown previously that high levels of IFN-beta were generated in vitro from spleen cells obtained from mice experiencing graft vs host disease (GVHD). However, very little or no IFN-gamma was found in these cultures even when IL-2 or Con A was added as a stimulant of IFN-gamma production. This study was undertaken to determine if the IFNs were similarly produced in vivo during the GVH reaction and to further explore the inability of GVHD spleen cells to produce IFN-gamma in vitro. GVHD was induced across minor histocompatibilities by the i.v. injection of B10.D2 spleen cells into sub-lethally irradiated BALB/c mice. Using cytoplasmic immunofluorescence to detect IFN-beta and -gamma, both IFNs were readily detectable in vivo in spleens of mice undergoing GVHD. IFN-gamma demonstrated a distinct distribution pattern, localizing in the peri-arteriolar lymphoid regions of the spleen, whereas IFN-beta immunofluorescence appeared diffusely in all areas. Expression of both IFN-beta and -gamma was shown to be dependent on the GVH reaction, inasmuch as syngeneic controls and mice given T cell-depleted donor cells had little immunofluorescence. These results contradict in vitro data in that IFN-gamma cannot be found in GVHD spleen cell cultures even in the presence of Con A. This in vitro unresponsiveness appeared to be due to the mixing of different cell populations as a result of preparing splenic single-cell suspensions. Percoll gradient fractionation of GVH spleen cells yielded a cell population which, when stimulated with Con A, produced IFN-gamma and underwent cell proliferation. This study represents the first description of the in vivo splenic distributions of IFN-beta and -gamma during GVHD, and presents data that suggest that in vitro results may not truly reflect in vivo immune responsiveness. Thus, the IFNs may play a critical role in the complex events leading to the GVHD syndrome.
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PMID:In vivo and in vitro production of IFN-beta and IFN-gamma during graft vs host disease. 314 98

In our laboratory, we have developed a murine model to examine GVHD across minor histocompatibility antigens. In our model, GVHD is induced by injecting B10.D2 spleen cells into irradiated BALB/c recipients. Seven to 10 days after irradiation and injection of cells, there are significant changes in cell function in the recipient spleens. In the B10.D2----BALB/c (600 rad) model, recipient spleen cells are profoundly unresponsive to Con A and LPS stimulation but show increased B cell activity measured by Staphylococcus aureus protein A plaque-forming activity. Spleen cells from such GVH mice profoundly suppress the mitogenic responses of normal BALB/c or B10.D2 spleen cells to Con A and LPS. The degree of impairment of the mitogenic response and the ability to suppress normal cells is proportional to the dose of cells used to induce GVH reactions. Both the inability to respond to mitogens and the capacity to suppress are also related to the dose of irradiation given to the recipients. In addition, immunosuppression across minor histocompatibility antigens shows an unevenhandedness. If we inject parental B10.D2 or BALB/c cells into F1 recipients (P----F1), there is greater inhibition of mitogenic responses when B10.D2 parental cells are given than when BALB/c cells are given to the irradiated F1 recipients. These experiments show that significant immunosuppression occurs during GVH reactions across minor histocompatibility barriers. The degree of suppression varies according to the dose of cells used to induce GVH, the dose of irradiation to the recipient and the "strength" of the GVH recognition system. Such experiments provide models for GVH disease seen in humans who receive treatment for leukemia or other diseases that involves recipient irradiation and infusion of HLA-identical bone marrow.
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PMID:Graft-vs-host reactions (GVHR) across minor murine histocompatibility barriers. I. Impairment of mitogen responses and suppressor phenomena. 315 67


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