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)

Several studies have investigated the role played by killer immunoglobulin-like receptors (KIRs) and their ligands on the outcome of hematopoietic stem cell transplantation (HSCT) in patients affected by oncohematologic diseases. However, the interpretation of the results of these studies is considerably hampered by the heterogeneity of the diseases, disease status at transplantation, and the different protocols employed for both conditioning and graft-versus-host disease (GVHD) prophylaxis. To better define the role of KIRs in HSCT, we studied KIR genotypes and HLA class I ligands in a homogeneous group of 45 thalassemia patients transplanted with bone marrow cells from an HLA-identical, unrelated donor. Patients that were heterozygotes for HLA-Cw groups 1 (HLA-Cw(Asn80)) and 2 (HLA-Cw(Lys80)) had a higher risk of developing acute GVHD than C1/C1 or C2/C2 homozygotes (relative risk [RR] = 8.75; 95% confidence interval [CI]: 1.63-46.76; P = .007). Vice versa, all patients who experienced primary/secondary graft failure were C1/C1 or C2/C2 homozygotes (RR = 20.45; 95% CI = 1.08-384.24; P = .009). Moreover, the presence of the HLA-A11 antigen conferred protection against GVHD (0% versus 35%, P = .02). Our results suggest that C1/C2 heterozygosity, may favor the development of donor alloreactivity and thereby increase the risk of GVHD. Conversely, C1/C1 and C2/C2 homozygosity seems to reduce the risk of GVHD but may increase the incidence of graft rejection. These data may be helpful in tailoring the intensity of GVHD prophylaxis and conditioning regimens in thalassemia patients receiving HSCT from an HLA-identical volunteer donor.
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PMID:Status of donor-recipient HLA class I ligands and not the KIR genotype is predictive for the outcome of unrelated hematopoietic stem cell transplantation in beta-thalassemia patients. 1795 Sep 22

We applied a cDNA expression screening procedure with cryopreserved non-clonal CD8+ T cell populations (Lennerz et al., Proc. Natl. Acad. Sci. USA 102:16013-8, 2005) to the identification of candidate antigens for graft-versus-host disease (GvHD) and graft-versus-leukaemia (GvL) effects in allogeneic haematopoietic stem cell transplantation (allo-HSCT). In a patient-donor model system with HLA class I disparities, we identified an HLA-B*44 mismatch allele, HLA-B*4405, as the dominant target of alloreactive T cells expanded in vitro from donor peripheral blood mononuclear cells (PBMC). HLA-B*4405-reactive T cells were detectable after multiple in vitro stimulations in the patient's post-HSCT PBMC. In a patient-donor model with full HLA compatibility, the major target antigen of donor lymphocytes stimulated in vitro with the respective patient's pre-HSCT PBMC was restricted by HLA-A*0201 and was encoded by TRIM22-442 C, a newly detected polymorphic allele of the tripartite motif family member TRIM22 (synonym: STAF50), preferentially expressed in cells of the haematopoietic system. An arginine(R)-to-cysteine(C) exchange at position 442 generated an immunogenic T cell epitope equivalent to a minor histocompatibility antigen (mHag). TRIM22-442C-specific T cells persisted long-term in the patient's post-HSCT PBMC. Approximately, 1.3% of Caucasians carry TRIM22.442 C in association with HLA-A*0201. In particular, the knowledge of a large and diverse panel of such mHags may be crucial for further improvement of donor selection and adoptive T cell transfer strategies. The procedure applied herein will help to accelerate and facilitate their identification.
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PMID:Dissection and molecular analysis of alloreactive CD8+ T cell responses in allogeneic haematopoietic stem cell transplantation. 1800 63

The past fifteen years have witnessed great progress in our undestanding of how natural killer (NK) cells function, their role in innate defenses and their possible exploitation in therapy. This contribution traces the major advances in these formerly mysterious cells, from the first discovery of HLA-class I-specific inhibitory receptors to a more recent major breakgthrough that highlighted important perspectives and major expectations regarding the cure of life-threatening leukemias. The key role of "alloreactive" NK cells in eradicating acute myeloid leukemias and in preventing both graft rejection and graft-versus-host disease, led to a true revolution in bone marrow transplantation. Thus, it is now possible to search for appropriate HLA class I mismatches to set NK cells in action to cure high risk leukemias.
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PMID:NK cell-mediated immune response against cancer. 1803 29

Delayed engraftment or graft failure is one of the major complications after cord blood transplantation (CBT). To investigate factors impacting engraftment, we conducted a retrospective analysis of adult patients who underwent reduced-intensity CBT at our institute, in which preparative regimens mainly consisted of fludarabine, melphalan, and total body irradiation with graft-versus-host (GVH) disease prophylaxis using single calcineurin inhibitors. Among 152 evaluable patients, the cumulative incidence of neutrophil engraftment was 89%. High total nucleated cell and CD34(+) cell dose were associated with the faster speed and higher probability of engraftment. In addition, the degree of human leukocyte antigen (HLA) mismatch in the GVH direction was inversely associated with engraftment kinetics, whereas no statistically significant association was observed with the degree of HLA mismatch in the host-versus-graft direction. Similarly, the number of HLA class I antigens mismatched in the GVH direction, but not in the host-versus-graft direction, showed a negative correlation with engraftment kinetics. HLA disparity did not have significant impact on the development of GVH disease or survival. This result indicates the significant role of HLA disparity in the GVH direction in the successful engraftment, raising the novel mechanism responsible for graft failure in CBT.
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PMID:Impact of HLA disparity in the graft-versus-host direction on engraftment in adult patients receiving reduced-intensity cord blood transplantation. 1953 97

A number of experimental studies have shown that natural killer (NK) cells can eliminate cancer cells and the mechanisms involved in this effect have been uncovered during the last two decades. Clinical data from haploidentical haematopoietic stem cell transplantation (haplo-HSCT) revealed that NK cells were responsible for remarkably favourable effects in both adult and paediatric high-risk leukaemias. NK receptors specific for major histocompatibility complex (MHC) class I molecules, including killer immunoglobulin (Ig)-like receptors (KIR) and CD94/NKG2A, play a major role in the anti-leukaemia effect (mediating either inhibitory or activating signals). Haplo- HSCT requires a heavy conditioning regimen for the patient and the use of large numbers of T cell-depleted HSC to be grafted. After transplantation, natural killer cells develop from HSC shortly after engraftment and may include 'alloreactive' NK cells that kill leukaemic cells and prevent graft-versus-host disease (GvHD). Alloreactive NK cells are characterized by the expression of KIR that are not engaged by any of the human leucocyte antigen (HLA) class I alleles expressed by the patient. Their generation is dependent upon the existence of a KIR/HLA class I mismatch between donor and recipient. Novel important information on the function and specificity of different KIR has been obtained recently by the analysis of donor-derived alloreactive NK cells in a cohort of paediatric patients given haplo-HSCT to cure acute, high-risk leukaemias.
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PMID:Activating and inhibitory killer immunoglobulin-like receptors (KIR) in haploidentical haemopoietic stem cell transplantation to cure high-risk leukaemias. 1966 39

In vivo assay to evaluate anti-cancer immunotherapy at the pre-clinical phase is eagerly needed. We currently established xenotransplantation-based method to analyze in vivo priming of cancer-antigen-specific human cytotoxic T lymphocytes (CTLs). We transplanted human peripheral T cells and analyzed priming of CTLs in NOG mice. Half of the mice engrafted with bulk lymphocytes including CD4(+) T cells died before analysis probably due to xenoreactive graft versus host disease. All of the mice engrafted with purified CD8(+) T cells survived until the analysis, and successful engraftment was observed in 80% of recipient mice. Thus, transfer of purified CD8(+) T cells is sufficient and safer than that of bulk lymphocytes. To add antigenic stimulation to the CD8(+) T cells in vivo, injection of antigenic peptide-loaded and monocyte-derived autologous dendritic cells (DCs) was simultaneously done and repeated 7 days later. The DC-based vaccinization resulted in efficient priming of HLA class I-restricted and MART1, WT1 or CMV peptides-specific CTLs in the recipient mice. This system may be useful to evaluate the stimulation of antigen-specific human CTLs in vivo.
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PMID:An in vivo model of priming of antigen-specific human CTL by Mo-DC in NOD/Shi-scid IL2rgamma(null) (NOG) mice. 1968 95

Given their antileukemic activity, natural killer (NK) cells can alter the outcome of hematopoietic stem cell transplantation (HSCT). The physiologic functions of NK cells are regulated by the interaction of killer immunoglobulin-like receptors (KIR) with specific HLA class I ligands. In the literature, different models based on HLA class I and/or KIR donor (D)/recipient (R) gene disparities are considered as predictors of NK cell alloreactivity. In this retrospective and multicentric French study, we analyzed the clinical impact of the different NK-alloreactivity models in 264 patients who underwent T repleted unrelated HSCT. First, we did not observe that the "KIR ligand-ligand" model had a significant clinical impact on unrelated HSCT outcome, whereas the "missing KIR ligand" model had a significant but limited effect on unrelated HSCT, because only the absence of C1 ligand in patients with myelogenous diseases was associated with a decreased overall survival (OS) (hazard ratio=2.17, P=.005). The "KIR receptor-receptor" and the "KIR receptor-ligand" models seemed the most capable of predicting NK alloreactivity because they had a significant impact on acute graft-versus-host disease (aGVHD) occurrence, OS, and relapse incidence in D/R unrelated pairs. In particular, KIR3DL1 gene mismatches in the GVH direction (D(+)R(-)) and the D KIR3DL1(+)/3DS1(+) and R Bw4(-) combination were respectively correlated with the lowest OS in HLA identical pairs (HR=1.99, P =.02) and the highest incidence of relapse in HLA nonidentical D/R unrelated pairs (HR=4.72, P =.03). Overall, our results suggest a detrimental effect of KIR3DL1(+)/3DS1(+) donor NK cells transplanted into HLA-Bw4(-) patients in the absence of an educational process via KIR3DL1/HLA-Bw4 interactions.
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PMID:Donor KIR3DL1/3DS1 gene and recipient Bw4 KIR ligand as prognostic markers for outcome in unrelated hematopoietic stem cell transplantation. 1982 95

HLA-mismatched grafts are a viable alternative source for patients without HLA-matched donors receiving ablative hematopoietic cell transplantation (HCT), although their use in reduced intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning HCT has been not well established. Here, we extended HCT to recipients of HLA class I-mismatched grafts to investigate whether NMA conditioning can establish stable donor engraftment. Fifty-nine patients were conditioned with fludarabine (Flu) 90 mg/m(2) and 2 Gy total body irradiation (TBI), followed by immunosuppression with cyclosporine (CsA) 5.0 mg/kg twice a day and mycophenolate mofetil (MMF) 15 mg/kg 3 times a day for transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSCs) from related (n = 5) or unrelated donors (n = 54) with 1 antigen +/- 1 allele HLA class I mismatch or 2 HLA class I allele mismatches. Sustained donor engraftment was observed in 95% of the evaluable patients. The incidence of grade II-IV acute and extensive chronic graft-versus-host disease (aGVHD, cGVHD) was 69% and 41%, respectively. The cumulative probability of nonrelapse mortality (NRM) was 47% at 2 years. Two-year overall and progression-free survival (OS, PFS) was 29% and 28%, respectively. NMA conditioning with Flu and low-dose TBI, followed by HCT using HLA class I-mismatched donors leads to successful engraftment and long-term survival; however, the high incidence of aGVHD and NRM needs to be addressed by alternate GVHD prophylaxis regimens.
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PMID:Low-dose total body irradiation and fludarabine conditioning for HLA class I-mismatched donor stem cell transplantation and immunologic recovery in patients with hematologic malignancies: a multicenter trial. 1990 May 71

Natural killer (NK)-cell alloreactivity in recipients of hematopoietic stem cell grafts from HLA-identical siblings is intriguing and has suggested breaking of NK-cell tolerance during the posttransplantation period. To examine this possibility, we analyzed clinical outcomes in a cohort of 105 patients with myeloid malignancies who received T cell-replete grafts from HLA-matched sibling donors. Presence of inhibitory killer cell immunoglobulin-like receptors (KIRs) for nonself HLA class I ligands had no effect on disease-free survival, incidence of relapse, or graft-versus-host disease. A longitudinal analysis of the NK-cell repertoire and function revealed a global hyporesponsiveness of NK cells early after transplantation. Functional responses recovered at approximately 6 months after transplantation. Importantly, NKG2A(-) NK cells expressing KIRs for nonself HLA class I ligands remained tolerant at all time points. Furthermore, a direct comparison of NK-cell reconstitution in T cell-replete and T cell-depleted HLA-matched sibling stem cell transplantation (SCT) revealed that NKG2A(+) NK cells dominated the functional repertoire early after transplantation, with intact tolerance of NKG2A(-) NK cells expressing KIRs for nonself ligands in both settings. Our results provide evidence against the emergence of alloreactive NK cells in HLA-identical allogeneic SCT.
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PMID:NK cells expressing inhibitory KIR for non-self-ligands remain tolerant in HLA-matched sibling stem cell transplantation. 2009 83

Many of the 51 serotypes of adenovirus have been associated with clinically relevant infection. Adenovirus can disseminate rapidly in patients with a compromised immune system, such as that which occurs secondary to haematopoietic progenitor-cell transplantation. The higher rate of infection in recipients of T cell-depleted grafts and in those undergoing T cell-targeted treatment during graft versus host disease demonstrates the importance of a T-cell response in preventing disseminated infection. Studies have shown that the memory response to adenovirus is directed primarily to the hexon protein and is dominated by CD4+ T cells, probably due to the ability of the virus to block its presentation on HLA class I antigens. We have developed an approach to expand adenovirus-specific T cells using a pool of overlapping pentadecapeptides derived from selected conserved regions of hexon. We characterized responses to identify the peptides that are recognized, the responding T-cell subsets and their HLA restriction. Of eight lines that were characterized extensively, seven included both CD4+ and CD8+ T cells and each recognized between two and eight unique peptide sequences. By focusing the response on the conserved sequences of hexon, the cell lines are likely to recognize most of the serotypes responsible for clinically relevant disease. The 15 aa peptides used to prime the responses are more likely than whole virus or longer peptides to expand the less frequent CD8+ memory subset. Lines prepared by using our method may be more effective in adoptive immunotherapy protocols designed to prevent or treat disseminated adenovirus infections in high-risk patients.
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PMID:Generation of cytotoxic T-cell lines using overlapping pentadecapeptides derived from conserved regions of the adenovirus hexon protein. 2013 Jan 35


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