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)

Endotoxin (lipopolysaccharide, LPS) treated with ferric chloride was tested for its potential as a non-toxic agent for enhancement of non-specific host resistance. A 1 mg dose of untreated endotoxin, injected i.p. into mice, resulted in 100 per cent mortality, whereas the same amount of chemically-treated endotoxin resulted in less than 35 per cent lethality. The radio-protective potential of the treated endotoxin was similar to that of untreated endotoxin, as 70 per cent of each group of mice tested with either substance survived a dose of 850 rad x-ray. Irradiated mice, challenged 8 days after 850 rad x-irradiation, died when injected with 25 mug of either untreated or treated endotoxin. Antibiotic decontamination of the intestinal tract of host animals reduced the possibility of toxicity from endogenous endotoxin after challenge. This treatment resulted in 100 per cent survival from a 25 mug challenge at 8 days post-irradiation. The ferric chloride-treated proved to be a more effective B-lymphocyte mitogen. At a dose of 100 mug, treated endotoxin resulted in a 50 per cent greater mitogenic stimulation of B-lymphocytes as compared with that found after exposure to untreated endotoxin. Several lines of evidence support the contention that tolerance to untreated endotoxin was induced by repeated injections of either endotoxin preparation 1) 100 per cent of all endotoxin-tolerant mice survived a 1 mg challenge dose of untreated endotoxin, 2) there was a reduced mitotic response of splenic B-lymphocytes after re-exposure with untreated endotoxin as compared with that observed for cells derived from saline-treated mice, and 3) all antibiotic decontaminated mice engrafted with spleen cells from mice made tolerant to either endotoxin preparation survive graft-versus-host disease. In conclusion, based on survival data from normal mice, ferric chloride-treated endotoxin is safer to use than normal endotoxin. Also, treated endotoxin can elicit biologic responses similar in magnitude to those found after injection of mice with untreated endotoxin.
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PMID:Evaluation of biologic activity of ferric chloride-treated endotoxin in mice. 23 54

The present data indicate that injection of LPS induces a decrease in thymus weight with selection of thymocytes more efficient in killer and helper activities. It has been reported (12) that two T-cell types may cooperate in the GVH reaction: the effector T1 and the amplifier T2. The maturation from T1 to T2 occurs mainly in the periphery, whereas immature cortex thymocytes differentiate to T1 within the thymus (13). Our results, showing an LPS-dependent enhancement of thymocyte killing activity, suggest that LPS selects thymocytes mostly of the T1 type. LPS-treated thymocytes are more efficient in the reconstitution of the anti-SRBC response. These data can be explained considering that LPS, like cortisone (14), enriches the thymus with more immunocompetent helper cells. Alternatively it may be suggested that LPS selects in the thymus cell populations characterized by high proliferative activity. Unpublished observations showing that LPS-treatment in vivo increases the in vitro response of thymocytes to Con-A are consistent with this interpretation.
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PMID:Cell selection in the thymus of mice treated with escherichia coli lipopolysaccharide (LPS). 77 31

Immunotoxicity studies have been performed on the photosensitizing agent Photofrin II (PHFR), a porphyrin derivative used in photodynamic therapy. Hybrid CD2F1 (H-2d/H-2d) or inbred C57Bl/6 (H-2b) male mice were injected with graded doses of the agent (from 1.2 to 12 mg/Kg ip) on day -5, -3 and -1 before assays. The animals, or spleen cells collected from them on day 0 with respect to PHFR treatment, were tested for: a) competence of producing GVHD upon cell transfer into allogeneic, immunosuppressed recipients; b) graft response against challenge with allogeneic lymphoma cells; c) delayed-type hypersensitivity (DTH) against sheep red blood cells; d) in vitro response to mitogens; e) NK cell activity; f) in vitro generation of alloreactive cytotoxic T lymphocytes (CTL); g) resistance against the challenge of a sublethal dose of Pseudomonas aeruginosa. Moreover the LD50 of the drug given ip has been determined in male CD2F1 mice. The results show that PHFR, even at the highest doses used, does not affect most of the immunological parameters studied, except for a marginal inhibition of CTL generation and increment in proliferative responses to Con A or LPS. These data along with parallel studies performed by our group on human models in vitro, showing increased susceptibility of PHFR-treated tumors to NK or LAK effector cells, point out that PHFR, in the absence of systemic photoactivation, is essentially non-immunotoxic in vivo and could render tumor cells more susceptible to natural immunity.
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PMID:Experimental studies of immunotoxicity of a photosensitizing agent (Photofrin II) in mice. 147 18

Cyclosporin A (CsA) is a potent inhibitor of cytokine (IL-2-IL-6, IFN gamma) production by CD4+ T lymphocytes stimulated via the T cell antigen receptor pathway. This action results in indirect inhibitory effects on the growth and differentiation of B lymphocytes (IL-4 and IL-6). Using experimental models, it has also been shown that the functional activities of mononuclear phagocytes (IFN-gamma) and other antigen-presenting cells, production of mast cells (IL-3) and eosinophils (IL-5) and the activity of natural killer (NK) cells may be inhibited indirectly by CsA. In addition, however, CsA blocks B cell responses to Ca(2+)-dependent signals (e.g., anti-IgM) downstream of phosphatidyl inositol diphosphate hydrolysis; Ca(2+)-independent responses (e.g., to LPS or IL-4) are largely unaffected. In general terms, the functions of macrophages are unchanged or reduced in the presence of CsA. These include phagocytic activity in vitro and in vivo, chemotactic migration, superoxide and H2O2 production, protein (including monokine) secretion and MHC gene product expression. Antigen presentation (e.g., by epidermal Langerhans cells) may be affected, especially at high drug concentrations. There is recent evidence that CsA inhibits mediator (histamine and prostaglandin) release from human mast cells and that mucosal mast cell numbers may be diminished in CsA-treated animals exhibiting graft-versus-host disease or helminth infections.
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PMID:The effects of cyclosporin A on non-T cell components of the immune system. 150 9

We studied the effect of depleting NK1.1+ cells from an allograft of lymph node and spleen cells on the outcome of GVH disease in the parent----F1-hybrid combination C57BL/6----(C57BL/6xDBA/2)F1. Four treatment groups were established: group I mice were transplanted with an unmodified graft from normal donors; group II mice were transplanted with an NK1.1-depleted graft that had been harvested from normal donors; group III mice received grafts from donors that had been injected with Poly I:C (100 micrograms i.p.) 18 hr prior to harvesting (These grafts were incubated with complement, but no antibody.); group IV mice were transplanted with depleted grafts harvested from donors that had received Poly I:C. Recipients in each group were monitored for splenomegaly, mitogen responsiveness, NK and CTL activity, histopathology, weight loss, and mortality. Results showed that recipients in all four groups developed splenomegaly and unresponsiveness to LPS, PHA, and Con A by day 12. Augmented host-derived NK activity and graft-derived antihost CTL activity was also demonstrated. Group IV showed little or no weight loss, minimal histopathological changes and a marked reduction in mortality. Recipients in all other groups developed features characteristic of GVH disease and exhibited a steady decline in body weight beginning by day 12. Mortality generally began on day 18 and reached 75-90% by day 60. We postulate that anti-NK1.1 depletes cells from the graft are intimately connected with the effector mechanism in acute GVH disease.
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PMID:Prevention of acute lethal graft-versus-host disease in F1 hybrid mice by pretreatment of the graft with anti-NK-1.1 and complement. 163 23

Irradiated C57BL/6(B6) mice, when they were injected with spleen cells of C57BL/6J-lpr/lpr(B6-lpr) mice, developed splenomegaly at 2 weeks post-transfer, but afterward displaced by GVH-like disease. At 2 weeks the enlarged spleen in the chimeric mice, designated as [B6-lpr----B6] chimera, contained about 70% of the total cell population as CD8-positive T cells. Spleen cells from [B6-lpr----B6] chimeras were unresponsive to Con A and LPS stimulation and suppressed the mitogenic response of B6, B6-lpr, and C3H spleen cells to Con A. However, they had no cytotoxic activity towards Con A blasts of B6 and B6-lpr spleen cells. The suppressor activity found in the [B6-lpr----B6] spleen cells was removed by pretreatment of them with anti-Thy-1.2 or anti-CD8(Lyt2.2) plus complement. The present experiment showed that enormous proliferation of CD8-positive suppressor T cells was induced in the [B6-lpr----B6] chimeras. These cells were probably responsible for the GVH-like lymphoid atrophy observed in these [B6-lpr----B6] chimeras.
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PMID:Analysis of the mechanism of graft-versus-host-like disease in B6 mice with transferred B6-lpr spleen cells. 171 58

After bone marrow transplantation many T-lymphocyte functions, including the production of cytokines (CK), such as interleukin 2, are severely depressed for months. The monocyte-derived cytokines tumor necrosis factor alpha and interleukin 6 are molecules central to immune functions. Moreover, they may be involved in graft-versus-host disease and in graft-versus-leukemia reaction. Hence, we have studied the reappearance of these CKs after BMT by analyzing whole blood cultures stimulated in vitro with lipopolysaccharide for 6 hr, followed by testing for the secretion of TNF in the WEHI 164/actinomycin D cytotoxicity bioassay and for IL-6 in the 7 TD 1 proliferation assay. We performed sequential studies in 6 children who were transplanted for aplastic anemia or leukemia with allogeneic bone marrow. We found that the production of both CKs can be induced as early as 10-14 days post BMT at the very beginning of engraftment, indicating that the regenerating monocyte system is recovering rapidly after BMT. Depletion and neutralization experiments confirmed that monocytes are the cellular source of the LPS-induced CK secretion after BMT. Control levels were reached 3 to 4 weeks post BMT. When analyzing the endotoxin-induced CK production in a larger panel of BMT patients after complete reconstitution, we could not detect any impact of acute or chronic GvHD, or of allogeneic or autologous BMT, nor did treatment with cyclosporine A (CsA) show any suppressive effect. Thus, our data show that the CK production of the monocyte/macrophage lineage is quite resistant to factors that do influence other cell lineages of the immune system during BMT. The coincident appearance of monocyte-derived cytokines and of GvHD suggests a role for these cytokines in GvHD in man.
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PMID:Recovery of monocytes after bone marrow transplantation--rapid reappearance of tumor necrosis factor alpha and interleukin 6 production. 192 48

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

We have been investigating the effects of polyinosinic:polycytidylic acid (pI:C), an interferon inducer, on the graft-versus-host reaction. We have previously shown that pI:C treatment of C57BL/6xAF1 (B6AF1) recipient mice immediately before injection of C57BL/6 (B6) parental lymphocytes inhibited the immuno-suppression and pathological changes normally caused by the GVH reaction, by a mechanism apparently identical to that seen in F1 hybrid resistance (HR) to hematopoietic grafts. We now demonstrate that delaying pI:C treatment by as little as 48 hr produces the opposite effect. Treatment of recipient B6AF1 mice at different days after transfer of parental lymphocytes induced a marked increase in the severity of the GVH reaction, as measured by a decreased plaque-forming cell response to sheep erythrocytes; decreased proliferative response to the T and B cell mitogens PHA, Con A, and LPS; increased pathological changes in both lymphoid and nonlymphoid tissues; and increased GVH-associated mortality. This effect is unrelated to HR, as pI:C was able to augment the severity of the GVH reaction when A strain cells were injected into AxCBAF1 recipients, which do not manifest HR. Early pI:C treatment (1 and 2 days after parental cell transfer) increased the severity of the GVH reaction much more than later pI:C treatment (7 and 8 days after parental cell transfer). This observation, along with the demonstration of altered pathology in GVH mice treated with pI:C, suggests that the effect of pI:C is not mediated through a direct suppressive effect of IF on the cells responding in either the PFC or mitogen assays, but rather by the ability of IF to activate or suppress mechanisms involved in the development of GVH-induced alterations.
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PMID:The effects of polyinosinic:polycytidylic acid on the graft-versus-host reaction. III: Increased severity of the reaction with delayed pI:C treatment. 274 89

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


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