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 found that murine lymphokine activated killer (LAK) cells have veto and natural suppressor activities in vitro, and prevent graft-versus-host disease (GVHD) in vivo. To determine whether human LAK cells mediate veto and natural suppression we measured their ability to inhibit generation of allospecific cytotoxic T cells (CTL) in mixed lymphocyte culture (MLC). When added to MLCs at low concentrations LAK cells caused veto-type inhibition: stimulator-type LAK cells inhibited generation of CTL but responder or third-party LAK cells did not. At higher concentrations LAK cells caused nonspecific inhibition: all three LAK cell types inhibited generation of CTL. LAK cell veto and natural suppressor activities were largely eliminated by irradiation with 30 Gy and by depletion of CD56+ cells, but increased after depletion of CD3+ cells. LAK cell veto activity is not likely an artifact of cold-target inhibition by the LAK cells themselves or by proliferation of T cells contaminating LAK cell preparations: (1) veto only occurred when LAK cells were added to MLC on days 0 through 2, but not when added on day 5; (2) addition of saturating numbers of labeled targets to fixed numbers of allo-CTL effectors failed to overcome the inhibitory effects of adding stimulator-type LAK cells at the onset of MLC; and (3) CD3-depleted LAK cells showed greater veto activity than threefold greater numbers of control LAK cells. In light of our previous findings in mice, the current results imply that adoptive immunotherapy with LAK cells may be useful in preventing GVHD in human bone marrow transplant recipients.
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PMID:Human lymphokine activated killer (LAK) cells suppress generation of allospecific cytotoxic T cells: implications for use of LAK cells to prevent graft-versus-host disease in allogeneic bone marrow transplantation. 137 Feb 6

Recent data in mice have shown that early administration of recombinant human interleukin-2 (rIL-2) provides significant protection from lethal graft-versus-host disease. Because of the potential clinical importance of these findings, it will be important to assess the effectiveness of this therapy in a large animal preclinical bone marrow transplantation model. We report here our initial studies of the in vitro and in vivo effects of rIL-2 in miniature swine. In vitro 4-day cultures of pig peripheral blood lymphocytes (PBL) in complete medium containing rIL-2 at 1,000 U/ml resulted in optimal proliferation and generation of lymphokine-activated killer (LAK) cells. A pig-mouse hybridoma cell line was found to be highly sensitive as a LAK cell target. Two naive pigs received 20,000 U/kg and 2 pigs received 100,000 U/kg of rIL-2 intravenously twice a day for 4 days. No clinical symptoms were seen during or after administration at the lower dose while both high dose-treated animals showed generalized erythema from days 2 to 4, and one showed mild diarrhea during this period. The disappearance of IL-2 activity from the serum showed two components: (1) an initial fast component with a half-time of approximately 10 min and (2) a slow component with a half-time of approximately 60 min. LAK cell precursors disappeared from the peripheral circulation by 6 min after rIL-2 administration and began to recover by 6 h in the low dose recipients and only after 12 h in the high dose recipients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro and in vivo effects of recombinant human interleukin-2 in naive miniature swine. 151 21

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

Cytomegalovirus (CMV) infection remains the commonest cause of infective death following allogeneic bone marrow transplantation (BMT). CMV disease post-BMT occurs in the context of compromised cellular defence mechanisms and is associated with marrow hypoplasia and pneumonitis. However, CMV infection induces release of interleukin 2 (IL2) which in turn generates MHC unrestricted lymphokine activated killer (LAK) cells. We have investigated whether recruitment of IL2 activated MHC unrestricted defence mechanisms post-transplant can be implicated in the marrow hypoplasia that frequently accompanies CMV infection. The results show that IL2 activated peripheral blood mononuclear cells (PBMC) have substantial cytotoxicity against MHC matched and MHC mismatched marrow fibroblasts but that this activity is not specific for CMV infected fibroblasts; uninfected target cells are also equally killed. Furthermore, post-BMT PBMC show greater responsiveness to IL2 than normal PBMC in killing of marrow fibroblasts. We provide a hypothesis from these observations which may explain some of the consequences of CMV infection post-BMT. Local production of IL2 activated cytotoxic cells which would be generated during CMV infection would damage uninfected as well as infected marrow fibroblasts and thereby could compromise haemopoietic growth factor production by marrow fibroblasts. Similarly generated cytotoxicity in the lung may accompany CMV pneumonitis. Our results suggest that administration of anti-IL2 receptor antibody may have a therapeutic role in CMV disease post-BMT as has recently been shown in graft-versus-host disease.
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PMID:IL2 activated killer cells may contribute to cytomegalovirus induced marrow hypoplasia after bone marrow transplantation. 164 63

T cell depletion has decreased the incidence and severity of graft-versus-host disease following transplantation of allogeneic bone marrow. In the treatment of leukemia, decreased GVHD has often been associated with diminished antileukemia or graft-versus-leukemia (GVL) reactivity resulting in higher relapse rates. However, we have not seen a loss of the GVL effect following transplantation of marrow grafts depleted of CD3+ T cells. This suggests that non-T-cell effectors may play a role in preventing leukemic relapse. To study whether natural killer and lymphokine-activated killer (LAK) activity in BM was compromised by T cell depletion, the effect of T-cell-specific monoclonal antibodies against CD3 and CD6 determinants alone, or in combination, on the generation and expansion of NK/LAK cells was examined in vitro and compared to the effect of T depletion on mitogen-driven T cell proliferation. Limiting dilution analysis revealed that T depletion with CD3 and/or CD6 specific antibodies significantly reduced the number of proliferating T lymphocytes but did not significantly affect the frequency of cells able to expand and mediate LAK activity. Bone marrow, depleted of CD3+ or CD6+ T cells, generated levels of LAK activity equivalent to non-T-cell-depleted bone marrow following long-term culture in recombinant interleukin 2. CD3- NKH-1+ cells were the predominant population in rIL-2 expanded marrow cultures prior to transplant and in the peripheral blood of patients who had received a CD3-depleted marrow graft 21-65 days earlier. These studies show that it is possible to selectively reduce GVH-reactive T cells in allogeneic bone marrow while retaining non-T-effector cells with potential to mediate an antileukemia effect in vivo.
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PMID:Preservation of lymphokine-activated killer activity following T cell depletion of human bone marrow. 169 9

The role of cytokines in the development of acute graft-vs-host disease (GVHD) was investigated in B6AF1 mice that were injected with parental A/J lymphocytes. Splenocytes from GVH mice exhibited an increased capacity to produce interleukin (IL)-1, IL-6, and TNF-a when stimulated in culture with lipopolysaccharide (LPS). This enhanced capacity was diminished following in vivo treatment with immunosuppressive drugs. Concanavalin A-stimulated GVH spleen cells produced significantly lower levels of IL-2 but higher levels of interferon-gamma (IFN-gamma) than did syngeneic spleen cells. Immunosuppressive therapy in vivo increased the capacity of GVH spleen cells to produce IL-2. However, immunosuppressants differed in their effects on IFN-gamma production. Sch 24937 (6-bromo-5-chloro-2-[1-(methylsulfonyl)acetyl] 3-(2-pyridyl)indole) enhanced or had no effect while cyclosporin A consistently decreased the capacity of splenocytes to produce this lymphokine. These results indicate that the capacity of GVH splenocytes for cytokine production can be differentially affected by the actions of some pharmacological agents. The data also indicate that there may be differential regulation of the production of IL-2 and IFN-gamma by the Th1 subset in the GVH spleen.
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PMID:A study of cytokine production in acute graft-vs-host disease. 190 99

We have used limiting dilution culture methods to determine the frequency of mitogen-responsive T cells in peripheral blood of patients after bone marrow autotransplantation, and have compared their responsiveness to that of allotransplant recipients and normal controls. Autotransplant patients were found to have low responder cell frequencies in tests for lymphokine-secreting helper function, and for IL-2 dependent proliferator and cytotoxic function. Multiple regression analysis showed that function was lower in autotransplant patients than in allorecipients, and lower in male patients for all three functional assays. Patients with clinically significant infection tended to have lower proliferative function in both transplant groups and lower cytotoxic function in the allotransplant population. Graft-versus-host disease was associated with lower T-cell function, but was present only in the allotransplant group; therefore, it cannot account for the even lower levels of function observed in the autotransplant population. Because we observe deficits in T-cell regeneration in autotransplant recipients that are even more severe than in allorecipients, we postulate that cellular immunodeficiency after bone marrow transplantation may reflect limitations in thymic-dependent repopulation rather than an effect of genetic disparity between host and donor (eg, clinical or subclinical graft-versus-host).
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PMID:Clonal analysis of T-cell deficiencies in autotransplant recipients. 201 8

Serum levels of interferon-gamma and the IFN-dependent marker molecules neopterin and beta 2-microglobulin were assessed in BMT recipients. Concentrations of the latter two markers were corrected for creatinine levels in order to eliminate the impact of alteration of kidney function. Serum levels were assessed daily using commercially available radioimmunoassays. Twelve patients were studied during the early phase of allogeneic bone marrow transplantation and eleven additional patients during complications of BMT. Results indicated that both the conditioning regimen for BMT as well as major clinical complications such as infection and acute graft-versus-host disease strongly influence the endogenous patterns of the lymphokine and its secondary messages. During allogeneic BMT IFN-gamma and neopterin levels exhibited a biphasic pattern with a first peak during conditioning with high-dose cyclophosphamide and a second still higher peak at the time of hemopoietic regeneration. beta-2-microglobulin ratios increased during conditioning and remained elevated throughout observation. Serious infections of bacterial and viral origin as well as GvHD were accompanied by elevated levels of all three serum parameters studied. The kinetics of enhanced endogenous production, however, differed between infectious complications and GvHD. Increasing concentrations were observed during infections subsequent to clinical manifestation, whereas they preceded disease manifestation in GvHD.
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PMID:Endogenous IFN-gamma during human bone marrow transplantation. Analysis of serum levels of interferon and interferon-dependent secondary messages. 217 Nov 63

The donor-derived immune system that forms after bone marrow transplantation (BMT) takes as long as 2 years to develop in healthy BMT recipients. Soon after BMT, GVHD and its treatment increase the susceptibility of the recipient to overwhelming infections, and they retard the development of the immune system. The new system develops from a primitive state characterized by cytotoxic and suppressive functions and progresses to a mature state characterized by the development of specialized lymphocyte functions such as lymphokine production, proliferation, and expression of growth factor receptors. These specialized functions develop in healthy long-term recipients, whereas the same functions may be absent or impaired in those who develop chronic GVHD.
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PMID:Immune recovery after bone marrow transplantation. 219 17

We studied the in vitro effects of lymphokine-activated killer (LAK) cells from the peripheral blood of chronic myeloid leukemia (CML) patients after allogeneic and syngeneic bone marrow transplantation (BMT). LAK cells were generated by incubating peripheral blood mononuclear cells from patients post-BMT with recombinant interleukin-2 (IL-2) (500 U/mL) in 10% AB serum for 7 days. They were phenotyped and tested for activity in a standard 4-hour 51Cr release assay (n = 37) and in a CFU-GM assay (n = 24). We found that the LAK cells were mainly activated natural killer cells, but some were CD3+ T cells. In the 51Cr release assay LAK cells from 20 of 33 (61%) allogeneic and 2 of 4 syngeneic recipients killed recipient CML cells and in 22 of 37 (60%) cases also killed the HLA disparate CML cells. In the CFU-GM assay the LAK cells incubated together with the CML cells in liquid culture before plating inhibited (P less than .05) colony growth in 16 of 22 allogeneic and 2 of 2 syngeneic recipients. Cell-cell contact was necessary for optimal effect. There was little or no inhibition of proliferation of donor marrow CFU-GM. This in vitro graft-versus-leukemia (GVL) effect could also be demonstrated after LAK effectors were depleted of CD3+ T cells. It was inducible in recipients of both T cell-depleted and T cell-replete donor marrow and in recipients with or without graft-versus-host disease. These results suggest that a major histocompatibility complex-unrestricted GVL effect is inducible following allogeneic and syngeneic BMT. The use of IL-2/LAK cells after BMT could reduce the risk of relapse.
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PMID:Induction of in vitro graft-versus-leukemia activity following bone marrow transplantation for chronic myeloid leukemia. 224 25


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