Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Immunohistochemical investigations were undertaken on paraffin-embedded tissue from the spleens of seven patients who had died after bone marrow transplantation (BMT) for leukemia. Parallel investigations were undertaken on three surgically resected traumatically ruptured (but otherwise normal) spleens and three spleens removed at autopsy from accident victims. 1) Up to ten weeks after BMT, the splenic lymphoid tissue was extremely atrophic. Lymphoid follicles (LFs) and periarteriolar lymphatic sheaths (PALS) were completely absent. A considerable increase in lymphoid cells in the red pulp and formation of small LFs and PALS occurred only in the longest surviving patient, who had died 50 weeks after BMT. 2) B cells (L26+, 4KB5+, Ki-B3+) were almost completely absent in the early post-transplantation period and thus T cells (UCHL1+) represented the major constituent of the hypoplastic splenic lymphoid tissue. Considerable numbers of T cells were already found two weeks after BMT. T-immune-accessory reticulum cells (S-100 protein+) were found in the PALS of the controls, but were absent in three of the BMT recipients. The findings clearly reflect the marked immunodeficiency in the early post-transplantation period, during which many patients (4/7 in this study) die of opportunistic infections, and are in line with the fact that the earliest signs of reconstitution of the immune system have been found to occur at three months post-transplantation. Since six of our BMT recipients had suffered from graft-versus-host disease our findings probably do not fully correspond to those when the immune system undergoes undisturbed reconstitution.
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PMID:Immunohistology of the human spleen after bone marrow transplantation for leukemia with special reference to the early post-transplantation period. 208 40

The effect of post-transplant immunosuppressive agents used in anti-GVHD prophylaxis on leukemic relapse was tested using a murine model of originally spontaneous, subsequently transplantable and non-immunogenic B cell leukemia (BCL1). (BALB/c x C57BL/6)F1 mice inoculated with 10(7) BCL1 cells were conditioned by total lymphoid irradiation (TLI) (1600 cGy), cyclophosphamide (200 mg/kg) or total body irradiation (TBI) 750 cGy and reconstituted with C57BL/6 (C57) bone marrow cells (30 x 10(6] or 10 x 10(6) bone marrow cells with additional 2 x 10(6) donor-type spleen cells, respectively. Mice were treated by cyclosporine A (CSA) 20 mg/kg i.p., or methylprednisolone (MP) 10 mg/kg i.p. for 10 days each and one group of controls received no post-transplant therapy. Stable chimerism was documented in all recipients with greater than or equal to 90% donor-type C57 cells in the peripheral blood. Eighty-nine percent of the mice treated by CSA following conditioning with TLI developed leukemia within 70 days, whereas none of the MP-treated mice and none of untreated chimeras showed any evidence of leukemia for more than 150 days. Adoptive transfer experiments using 10(5) spleen cells obtained from recipients conditioned with TBI were done to monitor residual leukemic cells following different post-transplant treatments. Eight-five percent of recipients of spleen cells obtained from mice treated with CSA developed leukemia in contrast with 33% and 25% when spleen cells were obtained from mice treated with MP or untreated controls, respectively (p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of cyclosporine A and methylprednisolone on the graft-versus-leukemia effects across major histocompatibility barriers in mice following allogeneic bone marrow transplantation. 208 96

HLA class II molecules may be induced on non-lymphoid cells by gamma-interferon (IFN-gamma). We investigated if HLA class II molecules induced by IFN-gamma on the HT29 colonic carcinoma cell line are functional, i.e. if they may be recognized by allogeneic T cells. We found that IFN-gamma-treated HT29 (HT29IFN) cells could not induce primary proliferative responses of peripheral blood T lymphocytes, nor were they able to induce proliferation in T-lymphocyte clones (TLC) specific for HLA class II molecules found on HT29IFN. However, in the presence of exogenous interleukin 2 (IL-2), 1 of 5 DQw8-specific TLC proliferated when restimulated with HT29IFN, and 3 of these 5 TLC could very effectively inhibit the growth of HT29IFN, probably due to a cytotoxic effect. Both the proliferative response and the cytotoxicity were inhibited by anti-DQ MoAb. We conclude that T cells may recognize HLA-DQ molecules on non-lymphoid cells, which may be of relevance for autoimmune diseases, graft-versus-host disease, and possibly for the recognition of malignant cells.
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PMID:T-cell recognition of HLA class II molecules induced by gamma-interferon on a colonic adenocarcinoma cell line (HT29). 211 Mar 80

In models of tolerance associated with mixed lymphoid chimerism, depletion of Thy 1+ cells from the allogeneic donor inoculum may decrease the level of chimerism achieved and the capacity of donor cells to induce tolerance. To determine whether the apparent role of Thy 1+ cells in the facilitation of bone marrow engraftment and induction of skin graft tolerance is related to alloaggression, the capacity of fully allogeneic C57BL/6J, H-2b BM cells to establish mixed lymphoid chimerism and skin graft tolerance in sublethally irradiated (2.5 Gy x 3) BALB/c, H-2d hosts was compared with that of semi-allogeneic BALB/c x C57BL/6J F1 H-2d/b BM cells which genetically lack the potential for graft-versus-host reactivity against parental recipients. The levels of mixed chimerism observed with allogeneic and semi-allogeneic F1 BM cells were nearly identical: 21.0 +/- 9.7% of spleen cells in H-2b BM-injected and 18.6 +/- 8.8% of spleen cells in H-2d/b BM-injected H-2d hosts were of donor allotype. There was no difference in the fraction of hosts rendered tolerant to C57BL/6J, H-2b skin grafts by H-2b vs. H-2d/b BM at either excess (94% vs. 92% tolerant) or threshold (37% vs. 40% tolerant) numbers of donor cells. Spleen cells from both types of mixed chimeras failed to respond to donor antigens in MLR. Both H-2b and H-2d/b BM-injected H-2d hosts rejected third party C3H/HeJ, H-2k skin grafts and responded to third party stimulators in MLR. Although these nonspecific allo-immune responses were not as strong as the responses of normal animals, they were suppressed to an equivalent degree in both types of chimeras. Graft-versus-host disease, if present in irradiated H-2b BM-injected hosts, did not significantly affect survival compared with survival of irradiated H-2d/b BM-injected animals. These results suggest that the tolerizing capacity of allogeneic BM does not depend upon GVHD and that allogeneic and semi-allogeneic BM establish mixed lymphoid chimerism and induce skin graft tolerance by similar mechanisms across a complete MHC disparity in sublethally irradiated adult hosts.
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PMID:Allogeneic versus semiallogeneic F1 bone marrow transplantation into sublethally irradiated MHC-disparate hosts. Effects on mixed lymphoid chimerism, skin graft tolerance, host survival, and alloreactivity. 213 69

We have used elutriation to deplete lymphocytes from the marrow allografts of 64 patients to date. The first phase I trial (1 x 10(6) lymphocytes/kg IBW) was designed to test the procedure for potential toxicities, most notably, graft failure. Study 2 (1 x 10(6) lymphocytes/kg, no CsA) was expected to reduce potential toxicity incurred from long term immunoprophylaxis while study 3 was aimed at reducing the incidence of GVHD by further reducing lymphocyte dose (5 x 10(5)/kg). Graft lymphocyte dose was based on morphologic determination and was subsequently confirmed by limiting dilution analysis and flow cytometry. Although grafts were standardized solely by lymphocyte dose, the product was more uniform than the original harvested BM with respect to other cell populations. Nearly all study I (n = 40) and study III (n = 20) patients engrafted with a median time to ANC greater than 500/ul of 19 days. Three of the 4 patients consecutively enrolled in study II failed to engraft, thus terminating the trial. While a moderate proportion of study I patients had AGVHD (44%) with attendant morbidity, only 20% of study III patients were found to have mild AGVHD (less than or equal to stage I). To date, this cohort has no organ or chronic GVHD and no GVHD-associated morbidity. Median follow-up times for patients in studies I and III are 27 and 11 months, respectively. Overall actuarial survival (n = 60) is 42% at 38 months (38% study I, 80% study III). Good prognosis study I patients experienced 45% actuarial survival versus 9% in the poor prognostic group. While lymphocyte depletion has been effective in reducing the incidence and severity of AGVHD, new strategies are needed to address the issue of disease relapse. As with other methods, lymphocyte depletion by elutriation caused an increased rate of leukemia relapse. The actuarial probability of remaining in remission for recipients of elutriated marrow containing 1 x 10(6) and 5 x 10(5) lymphocytes/kg, respectively, were 60% and 46% at 16 months. Elutriation provides a rapid, reproducible and flexible methodology for graft manipulation which has been effective in reducing the incidence and severity of AGVHD. However, if lymphocyte depletion is to fulfill its promise as a means of reducing the overall morbidity of allogeneic BMT, new strategies may be needed to address the issue of relapse. These may include changes in marrow ablative therapy and post-graft immunosuppression. Equally as important may be the ability to further manipulate accessory cells and lymphoid populations presently excluded from the graft.
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PMID:Using elutriation to engineer bone marrow allografts. 213 32

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

The induction of a chronic graft-versus-host (cGVH) disease in (Balb/c x A/J)F1 mice by the intravenous injection of either Balb/c or A/J parental lymphoid cells led to the development of two different models of disease. In this paper we compared the clinical aspects and the antigen specificities which recognized the autoantibodies developed by the animals of these two models of cGVH disease. Renal disease, alopecia, and purpura lesions were common in both models, although their frequency and intensity varied between groups. The models were differentiated by two main characteristics. When donor cells were of Balb/c origin, a joint disease similar to rheumatoid arthritis developed in 50% of the animals, and when donor cells were of A/J origin, 25% of the animals developed edema of the front feet, occasionally with loss of the nails, similar to that of scleroderma. Differences among the autoantibodies found in the sera of these two groups of mice were also observed. After the injection of Balb/c lymphoid cells, rheumatoid factors reactive with human and murine IgG were characteristically present (69 and 75%, respectively) and a statistically significant correlation was found between high titers of rheumatoid factor and arthritis (P less than 0.001). Antinuclear antibodies (ANAs) were present in all animals. Anti-dsDNA and anti-histones were positive in 50 and 25%, respectively. Anti-snRNP were detected at a low titer in 35% of the animals. When donor cells were of A/J origin, ANAs were also present in all mice. Anti-dsDNA, anti-histones, and anti-snRNPs antibodies were present in 90, 15, and 65%, respectively. The most outstanding characteristics among anti-snRNPs were the high titers of anti-U1 and anti-U3 detected in 50 and 30%, respectively. Rheumatoid factors reactive with human and murine IgG were positive in 15 and 42% of animals, respectively, but no significant correlation was found between these factors and disease. Our results indicate that the graft-versus-host disease induced in the same F1 strain of mice can be manifested in different forms of connective tissue disease, depending on whether the cells come from one or the other of the parental strains. Furthermore, in this paper the occurrence of rheumatoid factors in mice with cGVH is described for the first time.
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PMID:Different strains of donor parental lymphoid cells induce different models of chronic graft-versus-host disease in murine (Balb/c x A/J)F1 hybrid hosts. 214 68

Induction of a graft-versus-host (GVH) reaction (GVHR) in non-irradiated (C57BL/10ScSn x DBA/2)F1 mice (BDF1) with DBA/2 lymphoid cells leads to chronic GVH disease (GVHD). One of the pathological alterations of this type of GVHD is hyperplasia of host B cells with production of lupus-like autoantibodies. This hyperstimulation of host B cells has previously been demonstrated to be induced by alloreactive donor T helper cells that were also proposed to maintain it. We provide three pieces of experimental evidence in support of this concept. First, treatment of mice with chronic GVHD by injection of monoclonal anti-Thy-1.2 antibodies, performed at week 6 after the injection of C57BL/6 lymphoid cells into (C57BL/6 x C57BL.bm12)F1 mice led to a significant decrease in the titre of anti-nuclear antibodies. Second, CD4+ donor T cells persisted in BDF1 mice with GVHD (GVHF1) for at least 10 weeks after the induction of GVHR; these T cells showed alloreactive helper activity against H-2b MHC determinants of the opposite parent in vitro. Third, T cells of GVHF1 mice, obtained 2 months after the induction of GVHR and transferred into normal secondary recipients, induced signs of chronic GVHD in DBF1 but not in DBA/2 mice. The combined results show that persisting donor T helper cells in GVHF1 mice retain their alloreactivity towards H-2 class II antigens for a long time after the induction of GVHR and they strongly suggest that these T cells are also the driving force behind the production of lupus-like autoantibodies at the late stage of chronic GVHD.
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PMID:Persistence of allospecific helper T cells is required for maintaining autoantibody formation in lupus-like graft-versus-host disease. 214 86

The mechanism of transplantation tolerance in total lymphoid irradiation (TLI)-induced semiallogeneic bone marrow chimeras without clinical evidence of graft-versus-host disease (GVHD) was investigated using the technique of surgical parabiosis. When held in parabiosis with normal BALB/c mice, BALB/c---- (BALB/c x C57BL/6)F1 (BALB----F1) chimeras survived 7-9 days, significantly (P less than 0.001) shorter than the 12-19 day survival of normal F1 hybrids kept in parabiosis with normal BALB, and in contrast to indefinite (greater than 200 days) survival of syngeneic BALB parabiotic partners. When C57 skin grafts were placed on BALB mice held in parabiosis with BALB----F1 chimeras, C57 skin grafts survived 50-60 days, in contrast to 10-14 days in normal BALB recipients (P less than 0.001). Lethal GVHD, induced in sublethally irradiated F1 recipients by 10(7) BALB spleen cells, could not be delayed or prevented by cotransfer of 10(7) to 30 x 10(7) tolerant BALB spleen cells obtained from stable BALB----F1 chimeras. GVHD reactivity of BALB spleen cells isolated from BALB----F1 chimeras tolerant of C57 could not be recovered by depletion of Lyt2 cytotoxic suppressor cells. Taken together, in the absence of suppressive capacity by suppressor cells, these data support functional clonal deletion as the primary mechanism responsible for the maintenance of unresponsiveness to host alloantigens in TLI-induced semiallogeneic chimeras, since no protection against induction of GVHD could be documented in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The use of parabiosis for investigating the mechanism of transplantation tolerance in bone marrow chimeras induced by total lymphoid irradiation. 214 74

Using in-situ hybridizaiton, we showed the presence of the Epstein-Barr (EB) virus genome in epidermal cells from a patient with chronic lymphocytic leukemia and unusual cutaneous lesions characterized clinically by a maculopapular eruption and histologically by epidermal cell degeneration and lymphoid cell infiltration. Such histologic changes are similar to those seen in graft-versus-host disease. The EB virus genome was mainly detected in the basal, germinative cells of the abnormal epithelium. Specimens of our patient's healthy skin were negative. The presence of EB virus DNA in skin lesions was confirmed by polymerase chain reaction adapted for analysis of paraffin-embedded tissue. These findings indicate that EB virus can infect the human epidermis and that the viral infection may produce a distinctive cutaneous disease.
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PMID:Detection of Epstein-Barr virus in epidermal skin lesions of an immunocompromised patient. 215 77


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