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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

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

Graft-versus-host disease (GVHD) is known to cause profound dysregulation of the immune system, although its effector mechanisms are poorly understood. We now describe an effector lymphocyte of unusual phenotype in the skin of mice with GVHD. This cell is of donor origin and expresses several T-cell surface proteins including Thy-1, CD2, and CD4 but does not express CD8, CD3, NK1.1, or macrophage antigens. Mononuclear cells of this phenotype are the predominant lymphocyte in the epidermis of mice with GVHD 3 weeks after transplant but are not detected in transplanted mice without GVHD. Isolation and transfer of these lymphocytes into secondary recipients causes epidermal damage characteristic of GVHD. These data demonstrate that CD4+ CD8- CD3- lymphocytes are an important effector population that can be amplified outside the thymus and that can mediate target organ damage of GVHD.
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PMID:Lymphocytes with a CD4+ CD8- CD3- phenotype are effectors of experimental cutaneous graft-versus-host disease. 183 92

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

NK-like cytotoxicity in F1-hybrid mice with acute GVH disease is mediated by donor-derived CD3+/CD4-/CD8- cells that can lyse both NK-sensitive YAC-1 target cells as well as NK-resistant targets such as BW1100 and P815. Our objective was to determine whether this activity is mediated by gamma delta TCR+ cells. We showed that NK-like cytotoxic activity in the spleen and lymph nodes of mice with acute GVH disease could be depleted by indirect complement-mediated lysis using an Ab against gamma delta TCR. When purified NK1.1+ spleen cells that had been positively selected on a magnetic cell separator were used as effector cells, we found that NK-like cytotoxicity was mediated only by gamma delta TCR+ cells, suggesting that cells with NK-like activity are gamma delta TCR+/NK1.1+. We showed by flow cytometry experiments that coexpression of NK1.1 and TCR-gamma delta occurred on a large proportion of large granular lymphocytes in the spleens of GVH mice, but was not detectable in normal control mice. In GVH mice, fewer than 10% of small agranular NK1.1+ lymphocytes coexpressed NK1.1+ and gamma delta TCR+. On the basis of this hypothesis, we postulate that graft-derived large granular lymphocytes develop the NK1.1+/gamma delta TCR+ phenotype during the reaction, and that these cells play a role in the pathogenesis of acute GVH disease. We performed experiments to determine whether depletion of gamma delta T cells from donor mice affected the outcome of lethal GVH disease and found that there was a significant reduction in mortality.
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PMID:Gamma delta T cells in the pathobiology of murine acute graft-versus-host disease. Evidence that gamma delta T cells mediate natural killer-like cytotoxicity in the host and that elimination of these cells from donors significantly reduces mortality. 759 74

Interleukin 10 (IL-10) is a cytokine with both antiinflammatory and immunosuppressive properties. In the present study, we have examined the effects of recombinant human IL-10 (rHuIL-10) on the development of acute graft-vs.-host disease (GVHD) in unirradiated (C57B1/6JxA/J) F1 recipients of parental A/J lymphocytes. rHuIL-10 (2.5 to 100 micrograms/mouse administered subcutaneously) caused a significant reduction in splenomegaly in GVH mice. GVH splenocytes exhibited an augmented capacity to produce IFN-gamma when stimulated in culture with Con A or LPS. The IFN gamma produced in response to LPS stimulation was found to be derived from CD4+ and CD8+ T cells with little or no contribution from the NK1.1+ subpopulation of the GVH spleen. Treatment with IL-10 in vivo was found to diminish the capacity of splenocytes to produce IFN gamma when stimulated with LPS but not with Con A. IL-10 did not protect GVH mice from a lethal dose of LPS but caused a marked reduction in the serum TNF alpha response triggered by the LPS challenge. We conclude that IL-10 may be useful in controlling those clinical manifestations of acute GVHD that arise as a result of the activities of proinflammatory cytokines such as IFN gamma and TNF alpha.
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PMID:Inhibitory effects of recombinant human interleukin 10 on disease manifestations in a P-->F1 model of acute graft versus host disease. 770 86

Concurrent infection with MCMV has been observed to result in the marked exacerbation of a P-->F1 GVHR across a class I MHC only donor-recipient disparity. We have previously determined that MCMV induces several alterations characteristic of severe GvHR/D which are not observed during GvHR or MCMV infection alone. Most notable of these alterations is the enhanced development of donor anti-host cytotoxic T cell activity. The present studies were performed to examine the requirement of specific donor and host cell populations. Only depletion of donor CD8+ T cells (not NK1.1+ or CD4+) prevented development of severe GVHR/D. By in vivo antibody treatments, depletion of host CD4+ but not CD8+ T cells also abrogated the development of severe GVHR/D. These findings therefore support the hypothesis that MCMV-activated CD4+ T cells enhance the production of a donor anti-host class I CD8+ response. Thus, the present findings support hypotheses attributing the association of viral infection and GVHD development with pathogen-induced immune responses.
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PMID:CD8+ and CD4+ T cells contribute to the exacerbation of class I MHC disparate graft-vs-host reaction by concurrent murine cytomegalovirus infection. 809 96

Studies were performed to examine whether, in addition to T cells, there might be other immune cells also capable of exerting a graft-versus-leukemia (GVL) response following allogeneic marrow transplant. Using an MHC-matched mouse model, consisting of normal B10.S donors and SJL/J Rauscher-retroviral-leukemic recipients, the donor cells were selectively depleted of their Asialo-GM1+ component prior to being infused into the leukemic recipients. The incidence of relapse was then compared against that for matched leukemic control recipients of undepleted cells from the same donors. FCM analysis of the depletion protocol indicated that exposure to anti-Asialo-GM1 antibody eliminated more than half of the donor NK1.1+ cells, but caused no significant losses among the Thy-1+, CD3+, or CD8+ cells. Nevertheless, fatal relapse among the leukemic recipients of the depleted cells was nearly double that found among the leukemic control recipients of undepleted cells, 47.5 vs 25.4% (P = 0.01). In a parallel study, using normal SJL/J recipients, this same depletion protocol was found to have no significant effect on the incidence of graft-versus-host disease (GVHD). These results therefore suggest that Asialo-GM1+ NK cells may be capable of contributing to the suppression of relapse in this type of leukemic recipient of allogeneic marrow, and that this suppression may occur independently of GVHD.
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PMID:Evidence for a possible role of Asialo-GM1-positive cells in the graft-versus-leukemia repression of a murine type-C retroviral leukemia. 853 19

The feasibility of transplanting peripheral blood mononuclear cells (PBMC) from granulocyte colony-stimulating factor (G-CSF)-treated normal human donors to myeloablated allogeneic hosts has been demonstrated recently. The current work examined the ability of recombinant G-CSF to alter peripheral blood T-cell function and graft-versus-host disease (GVHD) in a murine model of allogeneic G-CSF-mobilized PBMC transplantation. Administration of recombinant G-CSF to C57BL/Ka mice markedly increased the capacity of PBMC to reconstitute lethally irradiated syngeneic hosts. T- and B-lineage lymphocytes were depleted about 10-fold in the bone marrow of the treated mice, and the T-cell yield in the blood was increased about fourfold. The ability of PBMC or purified CD4+ and CD8+ T cells to induce acute lethal GVHD in irradiated BALB/c mice was reduced after the administration of G-CSF. This was associated with decreased secretion of interferon gamma and interleukin-2 (IL-2) and an increased secretion of IL-4. The donor cell inoculum, which was most successful in the rescue of irradiated allogeneic hosts, was the low-density fraction of PBMC from G-CSF-treated mice. These low-density cells were enriched for CD4-CD8-NK1.1+ T cells and secreted about 10-fold more IL-4 than the unfractionated cells from the G-CSF-treated donors.
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PMID:Granulocyte colony-stimulating factor reduces the capacity of blood mononuclear cells to induce graft-versus-host disease: impact on blood progenitor cell transplantation. 920 83

Mice fall victim to GVHD when subjected to immunosuppressive treatment and injected with allogeneic bone marrow cells. A major population of cells associated with GVHD is known to be T cells. However, whether such T cells are of thymic or extrathymic origin is obscure. We applied two immunosuppressive conditions, 9 and 6.5 Gy irradiation, to C3H/He mice (H-2k). Bone marrow cells for injection were obtained from C57BL/6 (B6) mice (H-2b). The 9-Gy mice were reconstituted by lymphocytes of donor origin and showed GVHD, whereas 6.5-Gy mice were reconstituted by lymphocytes of recipient origin and showed mild GVHD. The liver was the organ where the reconstitution of lymphocytes occurred efficiently, and a major lymphocyte subset was intermediate (int) CD3 cells (i.e., CD3int cells) in both mice. CD3int cells had the properties of extrathymic T cells, showing the phenotype of NK1.1 + CD3int using invariant V alpha 14 chain. In 6.5-Gy mice, allogeneic cells were rejected by extrathymic T cells of recipient origin. The stored CD3int cells from the liver of 9-Gy mice evoked similar GVHD when transferred into 6.5-Gy irradiated C3H/He mice. These results suggest that CD3int cells of extrathymic origin are a major population for the induction of GVHD under immunosuppressive conditions.
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PMID:Intermediate TCR cells can induce graft-versus-host disease after allogeneic bone marrow transplantation. 963 79


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