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 investigated graft-versus-leukaemia (GVL) effects after allogeneic bone marrow transplantation (BMT), using three murine leukaemia models, A20 (B lymphocytic), WEHI-3 (myelomonocytic) and PU5-1R (myeloid). Injection of leukaemia cells in a high number (10(6) cells) into syngeneic Balb/c mice (H-2d) invariably led to death with a median survival time of 22 d (A20), 18 d (WEHI-3) and 45 d (PU5-1R). A lower tumour load of A20 (5 x 10(5) cells) was used in some experiments resulting in a leukaemic death rate of 94%. Lethal total-body irradiation followed by syngeneic BMT prolonged survival (P<0.05) for animals bearing the leukaemia A20 and WEHI-3 but was unsuccessful for animals injected with cells from the monocytic leukaemia PU5-1R. Graft-versus-host (GVH)-nonreactive marrow of (C57 x Balb/c)F1 mice (H2bxd) exerted a significant GVL-effect with reduced relapse rate and improved survival in mice receiving the leukaemia cell line A20. In animals with low tumour load a significant reduction of the relapse rate from 82% following syngeneic BMT to 47% following allogeneic, GVH-nonreactive BMT could be achieved. Depletion of natural killer (NK) cells from the GVL-reactive semi-allogenic bone marrow graft enhances the relapse rate of the leukaemia A20 to 65%. In mice bearing the leukaemias WEHI-3 or PU5-1R allogeneic GVH-nonreactive BMT did not improve survival compared to syngeneic BMT. Transplantation of GVH-reactive bone marrow from DBA mice (MHC identical to Balb/c, minor difference) caused only a limited and insignificant reduction of relapse rate for animals with the leukaemia A20. These in vivo data are in close correlation with in vitro natural killer cell (NK) activity of the donor strains against the respective leukaemia targets. Depletion of NK cells from the GVL-reactive (C57 x Balb/c)F1 bone marrow resulted in a significant loss of GVL activity. We conclude that NK cells are involved in graft-versus-leukaemia effects independent of graft-versus-host disease (GVHD).
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PMID:Graft-versus-leukaemia activity can be predicted by natural cytotoxicity against leukaemia cells. 863 41

A chimeric severe combined immunodeficient mouse engrafted with human peripheral blood (hu-PBL-SCID) model has been developed to test anti-T-cell monoclonal antibody (mAb) effects on systemic symptoms of the host and the survival of human skin grafts. To obtain consistent engraftment without lethal acute graft-versus-host disease (GVHD), SCID mice were pretreated with a combination of total body irradiation (2.5 Gy, day 0) and anti-asialo GM1 (anti-mouse natural killer cell) antiserum (50 micrograms i.p., day 3) before the intraperitoneal injection of 40-50 X 10(6) human PBL on day 4. With this protocol, the engraftment rate was 82% with 5-98% human CD45-positive cells in the peripheral blood. Mortality at 30 days was 0% in the mice bearing 5-50% human cells compared with 70% in those with more than 50%. Using hu-PBL-SCID mice with 5-50% human cells in their peripheral blood, we demonstrated the following results: 1) Human T cells isolated from these mice proliferated in response to immobilized OKT3 stimulation in vitro. 2) Hu-PBL-SCID mice but not normal SCID mice were able to reject human skin grafts in vivo 16-21 days after grafting. 3) Both OKT3 (anti-human CD3 mAb) and T10B9 (anti-human alpha beta T-cell receptor mAb) treatment prevented human skin graft rejection in hu-PBL-SCID mice. 4) OKT3 but not T10B9 induced first dose reactions characterized by hypothermia and hypoactivity which were consistently observed within 90 min of intravenous injection into hu-PBL-SCID mice. 5) Human cytokines were detected in the serum of the hu-PBL-SCID mice treated with anti-T-cell mAbs. The close similarity of these responses to human clinical mAb immunosuppressive therapy suggests that the hu-PBL-SCID mouse model may be an excellent tool for investigating the immunosuppression, side effects, and mechanism of action of agents that are specific for human and higher apes and not reactive with lower animals.
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PMID:A model of human anti-T-cell monoclonal antibody therapy in SCID mice engrafted with human peripheral blood lymphocytes. 936 54

We report a case of natural killer cell large granular lymphocytic (NK-LGL) leukaemia successfully treated with allogeneic peripheral blood stem cell transplantation (allo-PBSCT). The peripheral blood (PB) revealed an abnormal expansion of LGL that were CD3-, CD16- and CD56+, and had natural killer activity. In situ EBER-1 hybridization of the PB mononuclear cells showed the presence of Epstein-Barr virus (EBV) in the LGL as well as in lymphocytes infiltrating the tonsils and colon. Southern blotting with an EBV-terminal repetitive sequence probe demonstrated clonal proliferation of EBV+ cells. The patient received allo-PBSCT from his HLA-matched sister with a conditioning regimen involving the use of cyclophosphamide and fractionated total body irradiation. The patient promptly recovered trilineage haematopoiesis without graft-versus-host disease, and has been in complete remission without therapy for 10 months since allo-PBSCT, suggesting that allo-PBSCT could eradicate the NK-LGL leukaemic cells.
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PMID:Successful treatment of Epstein-Barr virus-associated natural killer cell large granular lymphocytic leukaemia using allogeneic peripheral blood stem cell transplantation. 967 65

Post-transfusion graft-versus-host disease (PT-GVHD) is a fatal adverse effect of blood transfusion. In spite of its severity, there is no effective treatment at present for PT-GVHD. Previously, we reported that chloroquine (CH) inhibited the cytotoxicity of cytotoxic T-cell (CTL) clones and tumour necrosis factor beta (TNF beta) production by TNF beta-producing clones in vitro, both the clones being derived from peripheral blood lymphocytes (PBMCs) of PT-GVHD patients. To explore the possibility of utilizing CH for the treatment of PT-GVHD, we extended our investigation of the immunosuppressive effects of CH in vitro to PBMCs derived from healthy donors. Our results show that CH inhibits the mixed lymphocyte reaction (MLR) between allogeneic PBMCs, production of inflammatory cytokines such as TNF alpha, interleukin-1 beta (IL-1 beta) and interferon gamma (IFN gamma) in mixed lymphocyte culture and natural killer cell activity, and, further, reduces the number of alloreactive CTL precursors.
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PMID:Immunosuppressive effects of chloroquine: potential effectiveness for treatment of post-transfusion graft-versus-host disease. 980 Feb 87

In comparison with HLA-matched sibling bone marrow transplants, unrelated donor transplants are associated with increased graft-versus-host disease and graft failure. This is likely in part due to HLA incompatibilities not identified by current matching strategies. High resolution DNA-based typing methods for HLA class II loci have improved donor selection and treatment outcome in unrelated donor bone marrow transplantation. By using DNA-based typing methods for HLA-A and -B on a cohort of 100 potential bone marrow donor/patient pairs, we find that serological typing for HLA class I is limited in its ability to identify incompatibilities in unrelated pairs. Furthermore, the incompatibilities identified are associated with the presence at high frequency of alloreactive cytotoxic T-lymphocyte precursors. DNA typing also indicates that HLA-C mismatches are common in HLA-A and -B serologically matched pairs. Such mismatches appear to be significantly less immunogenic with respect to cytotoxic T-lymphocyte recognition, but are expected to influence natural killer cell activity. Thus, improved resolution of HLA class I shows many previously undisclosed mismatches that appear to be immunologically functional. Use of high resolution typing methods in routine matching is expected to improve unrelated donor selection and transplant outcome.
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PMID:Molecular typing shows a high level of HLA class I incompatibility in serologically well matched donor/patient pairs: implications for unrelated bone marrow donor selection. 984 54

Seventeen cases (age at onset, 1 month to 18 years; M/F, 9/8) of hemophagocytic syndrome which received allogeneic hematopoietic stem cell transplantation (SCT) in Japan during the period 1988-1998 are reported. The patients consisted of six familial inheritance-proven erythrophagocytic lymphohistiocytosis (FEL), five familial inheritance-unknown and infective agents-unknown HLH (of which two were highly likely to have been FEL with characteristic CNS signs), and six aggressive Epstein-Barr virus (EBV)-related HLH (of which two were natural killer cell-type large granular leukemia/lymphoma-associated hemophagocytic syndrome, EBV-NK-LGLL-HPS). All cases were treated intensively with immuno-chemotherapy, or with chemotherapy before SCT. As sources of SCT, 12 cases received bone marrow cells (sibling six, father one, URD five), two cord blood, two purified CD34-positive cells, and one PBSC. SCTs were successful in all 17 cases, apart from one receiving CD34-positive SCT. Following SCT, four patients relapsed and five died with a median follow-up of 23 months. Among the relapsed cases, the two EBV-NK-LGLL-HPS previously published as successfully transplanted were included. Among the fatal cases, three patients died from relapsed active disease and the remaining two from fatal post-SCT EBV-positive T cell lymphoma and extensive chronic GVHD, respectively. As of the end of September 1998, 10 patients are alive without disease for 3.5 months to 147 months, while two post-SCT patients are still having therapy for residual/recurrent disease. The Kaplan-Meier analysis showed a 2-year event-free survival after SCT as 54.0+/-13.0%.
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PMID:Allogeneic hematopoietic stem cell transplantation for patients with hemophagocytic syndrome (HPS) in Japan. 1021 87

Interleukin (IL)-12 is a potent immunostimulatory cytokine and inducer of Th1 cell activity and of cytotoxic T lymphocyte and natural killer cell function. This cytokine also has anti-tumor activity. Although IL-12 has been shown to be an important pathogenic cytokine in the induction of graft-versus-host disease (GVHD), injection of exogenous IL-12 to murine allogeneic bone marrow transplantation (BMT) recipients paradoxically leads to a significant delay in the onset of GVHD mortality in fully MHC plus multiple minor antigen-mismatched strain combinations, and to complete inhibition of GVHD in a single haplotype-mismatched murine BMT model. IL-12-induced inhibition of GVHD is associated with reduced donor T cell activation and expansion, in part through an interferon (IFN)-gamma-mediated mechanism. Fas-mediated apoptosis of donor T cells also plays a significant role in IL-12-induced GVHD protection. Importantly, IL-12 preserves the graft-versus-leukemia (GVL) effect of allogeneic CD8 T cells against EL4, a host-type leukemia/lymphoma, while inhibiting GVHD. Like the protective effect against GVHD, the GVL effect in IL-12-treated mice is dependent on IFN-gamma. Thus, treatment with IL-12 leads to separation of GVHD-promoting and GVL effects of allogeneic BMT via an IFN-gamma-dependent mechanism.
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PMID:The role of interleukin-12 in preserving the graft-versus-leukemia effect of allogeneic CD8 T cells independently of GVHD. 1034 69

The innate immune system of severe combined immunodeficient (SCID) mice represents an important barrier to the successful engraftment of human cells. Different genetic and pharmacological strategies improve the graft survival. Non-obese diabetic (NOD)-SCID mice are better hosts for reconstitution with human peripheral blood leucocytes (Hu-PBL) because of their reduced natural killer cell and macrophage activity next to defective T and B cell functions. We investigated effects of TM-beta1, a rat monoclonal antibody recognizing the mouse IL-2 receptor beta-chain, on Hu-PBL survival and function in NOD-SCID and SCID mice. Relative to untreated littermates, TM-beta1 improved Hu-PBL survival in SCID and NOD-SCID mice. Moreover, TM-beta1-pretreated NOD-SCID mice displayed significantly better Hu-PBL survival and tissue distribution than TM-beta1-pretreated SCID mice. Irradiation of NOD-SCID mice further enhanced the effects of TM-beta1. However, these animals died within 3 weeks post-grafting due to graft-versus-host disease. Secondary immune responses were evaluated with Hu-PBL from a donor immune to hepatitis B surface antigen (HBsAg). In TM-beta1-pretreated NOD-SCID mice, human HBsAg-specific memory B cells produced high titres of anti-HBsAg immunoglobulin irrespective of the administration of a secondary antigen booster dose. This contrasts with secondary immune responses in TM-beta1-pretreated SCID mice where high titred antigen-specific immunoglobulins were produced when the appropriate antigen booster was given. In conclusion, reducing the function of the innate immune system in immunodeficient mice improves survival of the human graft and can result in an activation of the memory B cells without the need for recall antigen exposure.
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PMID:Mouse strain and conditioning regimen determine survival and function of human leucocytes in immunodeficient mice. 1060 88

We investigated the expression of natural killer cell receptors (NKRs) for HLA-C on peripheral blood mononuclear cells (PBMCs) in 23 allogeneic bone marrow transplantation (allo-BMT) patients to analyse the role of NKRs in alloresponse concerning graft-versus-host disease (GVHD). CD158a expression was low and there was little change in the expression after allo-BMT. Also, there was no difference in the proportion of CD158a+/CD3- after allo-BMT. In contrast, the proportion of CD158b+/CD3- cells, mainly NK cells, increased in the early stage (< 2 months) after allo-BMT and then gradually decreased (3.3 +/- 2.6% before BMT vs. 15.4 +/- 8. 6% in the early stage after BMT, 8.5 +/- 4.9% during the period 3-6 months after BMT and 7.0 +/- 3.0% > 6 months after BMT; P < 0.05). However, CD158b expression on CD3+ T cells increased 3 months after allo-BMT (1.1 +/- 1.1% before BMT vs. 5.1 +/- 7.7% during the period 3-6 months after BMT and 3.0 +/- 2.4% > 6 months after BMT, P < 0. 05). The highest percentages of CD158 expression in patients without chronic GVHD (cGVHD) and those with cGVHD were compared. The percentage of CD158b+/CD3+ cells and also that of CD158b+/CD8+ cells were significantly increased in patients with cGVHD compared with those in patients without cGVHD (2.6 +/- 2.0% vs. 8.0 +/- 11.2% and 2.3 +/- 1.5% vs. 8.3 +/- 11.7% respectively; P < 0.05). The exact clinical relevance of these CD158b-expressing cells is not clear. However, there is an interesting possibility that CD158b-expressing cells play some role in the regulation of GVHD after allo-BMT.
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PMID:Expression of HLA-C-specific natural killer cell receptors (CD158a and CD158b) on peripheral blood mononuclear cells after allogeneic bone marrow transplantation. 1079 83

We have sequentially investigated the expression of natural killer cell inhibitory receptors (KIRs) for HLA-C (CD158b) on peripheral blood mononuclear cells (PBMC) in three patients with extensive chronic graft-versus-host disease (cGVHD) after allogeneic bone marrow transplantation (alloBMT). Clinical symptoms of cGVHD were not cured and worsened in the first patient whose CD158b-positive cells increased to 18.5% during cGVHD and decreased to 9.4% at 8 months after transplantation. On the other hand, cGVHD was cured and did not relapse in the second patient whose CD158b-positive cells increased up to 45.9% during cGVHD and sustained 19.4% at 8 months after transplantation. In contrast, CD158b-positive cells were less than 10% during the course of cGVHD in the third patient, and her cGVHD did not respond to treatment. Therefore, it appears that chronic allostimulation augments the expansion of CD158b-positive cells and these expanded CD158b-positive cells may have some role in the control of alloresponse in some patients.
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PMID:Sequential analysis of HLA-C-specific killer cell inhibitory receptor (CD158b) expressing peripheral blood mononuclear cells during chronic graft-versus-host disease. 1096 67


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