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)

In our model of murine BMT, the lethal GVHD which develops against DBA/2 host incompatible minor histocompatibility antigens (mHAgs) can be prevented by donor preimmunization before grafting. Recipient mice become long survivors (LS mice) and tolerant to host mHAgs. However, a GVL effect is preserved and mediated by CD8+ CTL able to kill P815 tumor cells in vitro and in vivo. To explain why a GVL exists without GVHD, we compared the CTL activity of LS and B10.D2 donor mice after immunization with DBA/2 spleen cells or with P815 cells. Experimental results indicated that: (1) the level of cytotoxicity for H-2b incompatible cells was similar in LS and B10.D2 mice; (2) CTL recognizing host DBA/2 mHAgs, whose expression is restricted to the spleen or is shared between spleen and P815 cells, were partially unresponsive in LS mice; (3) P815 injection into LS mice predominantly generated CTL specific for antigens restricted to P815 cells, the repertoire of which was not tolerized. Characterization of TCR beta chain showed that the diversity of Vbeta and Jbeta usage by CD8+ T cells activated after P815 injection is considerably restricted in LS mice, compared to B10.D2 donor mice. These results indicated that the GVL effect in LS mice involved mainly T cells specific for tissue-restricted antigens expressed on P815 cells and not on normal DBA/2 spleen cells. In addition, the absence of GVHD may be attributed to the unresponsiveness of CD8+ CTL specific for host mHAgs expressed on DBA/2 spleen cells.
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PMID:CD8+ cytotoxic T cell repertoire implicated in grafts-versus-leukemia effect in a murine bone marrow transplantation model. 1033 53

LF 08-0299 (Tresperimus), a novel immunosuppressive compound, has been previously shown to prevent graft-versus-host disease in murine models. In this study, we investigated the influence of LF 08-0299 on the TCR Vbeta repertoire of irradiated F1 recipient mice reconstituted with either syngeneic or parental bone marrow cells. We showed that a partial blockade of thymic differentiation occurred in normal mice under treatment at the transition CD4-/CD8- to CD4+/CD8+, and that this blockade was fully reversible. Despite the effect on the thymus, normal T cell repertoire negative selection was preserved following syngeneic bone marrow transplantation. We further assessed whether LF 08-0299 administration could modify Vbeta T cell expression in irradiated recipients reconstituted with parental bone marrow cells. In our murine parental to F1 transplant model, abnormal TCR Vbeta3, Vbeta5, Vbeta6 and Vbeta11 expression was demonstrated in peripheral lymph nodes of irradiated recipients. Moreover, Vbeta6 and Vbeta3 T cell populations were overexpressed. Administration of LF 08-0299 modified the pattern of Vbeta T cell expression. The expansion of Vbeta6 T cells was selectively inhibited under LF 08-0299 therapy and, in contrast, Vbeta5 T cells were overexpressed. Lymph node histological analysis showed that LF 08-0299 administration fully prevented the graft-versus-host reaction occurring in untreated recipient mice.
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PMID:T cell repertoire expression in murine recipients of bone marrow transplant after LF 08-0299 (Tresperimus) administration. 1034 35

Donor T cells that are activated by host alloantigens initiate graft versus host disease (GVHD) but their long-term fate is poorly understood. The behavior of alloreactive donor T cells was studied in sublethally irradiated SCID mice. Intravenous injection of 10(6) allogeneic lymphocytes caused a severe form of GVHD, characterized by host hematopoietic atrophy. Fifty-fold fewer donor cells did not induce disease and were not simply rejected by radioresistant host mechanisms. Instead, low numbers of allogeneic T cells expanded 20- to 50-fold and remained for >1 year without causing evidence of GVHD. Persistent non-cycling donor cells with an activated phenotype were mainly found in the spleen. Tolerance was inferred by the recovery of host hematopoiesis, despite the presence of donor allogeneic T cells, and the inability of long-term persisting donor T cells to mediate cellular cytotoxicity or proliferate in response to exogenous IL-2 or antigenic stimulation in vitro. The TCR density of long-term persisting donor T cells was down-regulated. These findings suggest that the development of GVHD depends on the magnitude of the initial anti-host response. Subsequently donor cells differentiate, over several months, into a senescent-like state. This behavior questions the rationale for current treatment approaches to GVHD and is of relevance to any clinical situation where chronic T cell activation takes place in the absence of thymic development.
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PMID:Long-term persistence of IL-2-unresponsive allogeneic T cells in sublethally irradiated SCID mice. 1050 78

We have initiated a phase I/II clinical trial, involving the use of herpes simplex thymidine kinase gene (HS-tk)-expressing donor primary T cells, in order to modulate the graft-versus-host disease (GvHD) occurring after allogeneic hematopoietic stem cell transplantation. The preparation of gene-modified T cells (TkTCs) required a 12-day ex vivo culture comprising an initial OKT3 and IL-2 stimulation, a retrovirus-mediated transduction, and a 7-day selection step in the presence of G418 and IL-2. The low transduction efficiency as well as the culture conditions may significantly alter the diversity of the T cell repertoire. We therefore examined the T cell repertoire of HS-tk-expressing T cell samples from 11 different donors by the Immunoscope method. This method analyzes the hypervariable region of the T cell receptor beta chain (TCRBV) by amplifying the complementarity-determining region 3 (CDR3) and determining size diversity. In all examined samples (four of which were infused into patients), all TCRBV subfamilies were represented with, however, a significant skewing within a minority of subfamilies. Kinetic studies demonstrated that this skewing appeared between day 7 and day 12, with dates of appearance variable from one subfamily to another. In addition, the repertoire analysis of two different culture products, harvested and produced at different times from the same donors, suggested that some repertoire abnormalities could be donor specific. Quantitative analysis revealed no major modifications in gene usage, even in skewed TCRBV subfamilies, with a few clonal expansions concerning a limited number of TCRBV subfamilies. Importantly, identical abnormalities were found in control cells grown in parallel under similar conditions but not transduced or selected, thus demonstrating that these abnormalities were not related to the transduction or the selection process, but rather to the ex vivo culture. The initial stimulus used for T cell activation is a major source of TCRBV perturbation, since replacing the OKT3 + IL-2 stimulus by CD3 + CD28 monoclonal antibody-coated beads prevented the occurrence of alterations. Overall, the HS-tk-expressing T cells used in our clinical trial exhibit limited TCR repertoire skewing that is not due to the transduction/selection procedure. However, future T cell gene transfer protocols for clinical trials should be designed to take into account or possibly prevent such T cell repertoire alterations.
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PMID:Retrovirus-mediated gene transfer in primary T lymphocytes: influence of the transduction/selection process and of ex vivo expansion on the T cell receptor beta chain hypervariable region repertoire. 1083 17

Post-transplant lymphoproliferative disorder (PTLD) is uncommonly of T cell origin, especially following BMT. We describe a 13-year-old boy with severe aplastic anemia (SAA) and no evidence of Fanconi's anemia who underwent BMT at 11 years of age using CY 10 mg/kg once daily i.v. on days -5, -4, antilymphocyte globulin (ALG) 30 mg/kg once daily i.v. on days -5 approximately -3 and CsA from day -1 as conditioning. The BMT failed and he received a further peripheral blood stem cell transplant (PBSCT) 240 days after BMT. Conditioning was with CY 50 mg/kg once daily i.v. on days -5 approximately -2, and ALG 15 mg/kg once daily i.v. on days -4 approximately -2. GVHD prophylaxis included CsA and MTX. Engraftment was later confirmed by cytogenetic studies. Desquamation and ulcers of the oral mucosa and mouth angle developed in the 13th month post PBSCT. A buccal mucosa biopsy on day +524 revealed only plasmacytosis. Immunosuppressants were discontinued at that point. Generalized lymphadenopathy, prolonged fever (waxing and waning) and facial swelling developed in the 18th month post PBSCT. A neck lymph node biopsy on day +601 showed T cell lymphoma of diffuse large cell type with monoclonal TCR gamma-chain gene rearrangement. A FISH study showed that the malignant T cells were of recipient origin. EBV in situ hybridization was negative. He did not receive further treatment apart from discontinuation of immunosuppressants. He was followed up in our out-patient clinic and showed good performance 1170 days post PBSCT. We speculate that a different mechanism was operating in the pathogenesis of T cell lymphoma in this case. Risk factors include SAA and two transplants, conditioned with CY and ALG, long term use of CsA and treatment with azathioprine.
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PMID:T cell lymphoproliferative disorder following bone marrow transplantation for severe aplastic anemia. 1108 91

It is known that the liver is a major hematopoietic organ at fetal stages, but the hematopoiesis of this organ ceases at birth. However, the liver is still found to comprise c-kit+ stem cells and gives rise to extrathymic T cells, NK cells, and even granulocytes after birth. Extrathymic T cells generated in the liver of mice are identified as intermediate TCR (TCRint) cells, which include the NK1.1+TCRint (i.e. NKT cells) and NK1.1-TCRint subsets. Although extrathymic T cells are few in number during youth, they increase in number with advancing age. The number and function of extrathymic T cells are also elevated under conditions of stress, infections, malignancy, pregnancy, autoimmune diseases, chronic GVH diseases, etc. Under these conditions, the mainstream of T cell differentiation in the thymus, which produces conventional T cells, is inversely suppressed. Extrathymic T cells comprise self-reactive forbidden clones and mediate cytotoxicity against abnormal self-cells. Therefore, they might be beneficial for the elimination of such cells. However, over-activation of extrathymic T cells might be responsible for the onset of certain autoimmune diseases.
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PMID:Extrathymic pathways of T cell differentiation. 1134 23

Pulmonary inflammation is one of the risk factors associated with blood and marrow transplantation (BMT). To determine the potential role of T cells in pulmonary complications after transplantation, we analyzed the T-cell repertoire expressed in bronchoalveolar lavage fluids from eleven patients with graft-versus-host disease following BMT. A reverse transcriptase-polymerase chain reaction was used to amplify rearranged TCR transcripts in unfractionated, CD4+, and CD8+ T cells from bronchoalveolar lavage fluids. The relative expression of TCR variable (V) gene families and the diversity of junctional region lengths associated with different AV and BV gene families were analyzed. Nearly all TCR AV and BV gene families were detected in bronchoalveolar lavage cells from BMT recipients. Oligoclonal patterns of TCR junctional region lengths were observed in unfractionated, CD4+, and CD8+ bronchoalveolar T cells. The oligoclonal expansion of bronchoalveolar T cells in patients was confirmed by DNA sequencing. TCRV gene expression is almost completely restored in the lungs of BMT recipients as early as two weeks after transplantation. Increased oligoclonality among TCR gene families suggests either an incomplete restoration of TCR diversity or an antigen-driven expansion of T cells in the lungs of BMT recipients with graft-versus-host disease, not necessarily related to pulmonary infection.
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PMID:Pulmonary T cell repertoire in patients with graft-versus-host disease following blood and marrow transplantation. 1142 85

Cytotoxic T lymphocytes (CTL) are thought to play an important role in the graft-versus-leukemia (GVL) response. Unfortunately, GVL reactivity is often associated with life-threatening graft-versus-host disease (GVHD). Characterization of CTL that selectively attack leukemic cells but not normal cells may lead to the development of adjuvant immunotherapy that separates GVL from GVHD. Here, we describe TCR gamma delta (V gamma 9/V delta 1) CTL, isolated from the peripheral blood of an AML patient after stem cell transplantation (SCT), that very efficiently lysed freshly isolated acute myeloid leukemia (AML) cells and AML cell lines. Interestingly, HLA-matched non-malignant hematopoietic cells were not killed. We revealed that the killer cell-inhibitory receptor (KIR) p58.2 (CD158b) specific for group 2 HLA-C molecules negatively regulates the cytotoxic effector function displayed by these TCR gamma delta CTL. First, an antibody against HLA-C enhances lysis of non-malignant cells. Secondly, stable transfection of HLA-Cw*0304 into the class I-negative cell line 721.221 inhibited lysis. Finally, engagement of p58.2 by antibodies immobilized on Fc gamma R-expressing murine P815 cells inhibits CD3- and TCR gamma delta-directed lysis. Compared to non-malignant hematopoietic cells, AML cells express much lower levels of MHC class I molecules making them susceptible to lysis by p58.2(+) TCR gamma delta CTL. Such KIR-regulated CTL reactivity may have a role in the GVL response without affecting normal tissues of the host and leading to GVHD.
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PMID:TCR gamma delta cytotoxic T lymphocytes expressing the killer cell-inhibitory receptor p58.2 (CD158b) selectively lyse acute myeloid leukemia cells. 1143 26

To study the influence of antigen density on the efficiency of negative selection in the thymus, MHC class I (H-2K(b), K(b)) transgenic mice were generated, which expressed a K(b) transgene under the control of its natural promoter at 33% (K(b-lo)) or 150% (K(b-hi)) the surface density of Kb in C57BL/6 (B6, H-2(b)) mice. These mice were crossed to anti-K(b) T-cell receptor (Des-TCR) transgenic mice. In Des-TCRxK(b-hi) double transgenic mice, Des-TCR bearing T cells were completely eliminated during thymocyte maturation. In contrast, in Des-TCRxK(b-lo) double transgenic mice, two populations of Des-TCR T cells were evident, which either expressed the Des-TCR at intermediate density in the absence of CD8 (Des-TCR(int)CD8(-)) or expressed both the Des-TCR and CD8 at low density (Des-TCRloCD8lo). In the thymus of both types of double transgenic mice, no Des-TCR(+)CD4(+)CD8(+) thymocytes were detected, suggesting that deletion of Des-TCR cells occurred before the CD4(+)CD8(+) stage. Because only very few Des-TCR(+) thymocytes were found in Des-TCRxK(b-hi) transgenic mice, deletion of these T cells apparently occurred upon expression of the Des-TCR. By contrast, Des-TCRxK(b-lo) transgenic mice showed distinct populations of Des-TCR(int)CD4-8- and Des-TCR(lo)CD8(lo) thymocytes, suggesting that expression of the CD8 coreceptor was required to allow negative selection to proceed. Functional analyses showed that sublethally irradiated Des-TCRxK(b-lo) double transgenic mice were protected from lethal graft-versus-host disease by injected Des-TCR lymph node cells.
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PMID:Ligand density determines the efficiency of negative selection in the thymus. 1147 58

Donor regulatory T cells (CD3+ alphabetaT-cell receptor [TCR]+) derived from the repopulating host thymus have been shown to be primarily responsible for suppression of GVHD following DLI therapy in murine BMT models. However, natural killer (NK) T cells also have regulatory properties, and a role for NK T cells in suppression of GVH reactivity has not been completely excluded. NK cells may also contribute to the graft-versus-leukemia (GVL) effect associated with DLI therapy. In this study, we used a murine BMT model (C57BL/6 into AKR) to study whether depletion of donor NK cells had any impact on the suppression of GVH reactivity after DLI or on the DLI-induced GVL effect against acute T-cell leukemia. Depletion of donor NK cells was accomplished in vivo by giving DLI-treated bone marrow chimeras multiple injections of anti-NK1.1 monoclonal antibody (MoAb). The chimeras treated with anti-NK1.1 MoAb had significantly fewer splenic NK1.1 cells than nontreated chimeras, and splenocytes from anti-NK1.1-treated mice were deficient in the ability to generate lymphokine-activated lytic activity. Results presented here showed that NK-cell depletion had no effect on the suppression of GVH reactivity after DLI. When DLI-treated chimeras were challenged with an acute T-cell leukemia, NK-cell depletion had no discernible effect on GVL reactivity. These preclinical data suggest that donor NK cells do not have a significant role in the suppression of GVHD after DLI or in the mediation of GVL reactivity induced by DLI.
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PMID:Donor natural killer (NK1.1+) cells do not play a role in the suppression of GVHD or in the mediation of GVL reactions after DLI. 1176 Jan 46


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