Loss or downregulation of HLA class I expression at the allelic level in acute leukemia is infrequent but functionally relevant, and can be restored by interferon

Brouwer, Rolf E.; Heiden, Pim van der; Schreuder, G. M. T.; Mulder, Arend; Datema, Gert; Anholts, J.; Willemze, R.; Claas, Frans H.J.; Falkenburg, J. H. F.

doi:10.1016/s0198-8859(01)00381-0

Cited by 73 publications

(67 citation statements)

References 28 publications

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“…This antigen presentation defect is restricted to a very limited number of antigens, namely those affected by the chromosomal aberration. It differs thereby from previously described immune escape mechanisms like loss/downregulation of HLA expression 6 or peptide processing defects, 7 which broadly abolish antigen recognition on malignant cells. Consequently, the observed mechanism of mHag loss requires particular attention when targeting specific mHags with immunotherapy.…”

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confidence: 62%

“…In our current study published in Leukemia, 6 we did not have the chance to identify the JAK2 V617F mutation during the MDS phase lacking myelofibrosis. We detected the mutation in the myelofibrosis phase; therefore, we considered that the difference of the JAK2 V617F mutation, 6 unlike the contention of Kremer et al, 3 might mainly be owing to different diagnostic categorization.…”

mentioning

confidence: 69%

“…We detected the mutation in the myelofibrosis phase; therefore, we considered that the difference of the JAK2 V617F mutation, 6 unlike the contention of Kremer et al, 3 might mainly be owing to different diagnostic categorization. Owing to the lack of a concrete diagnostic definition of MDS with myelofibrosis, we cannot completely eliminate the possibility of overestimating 'true' MDS with myelofibrosis, but we do not know the biological or definite clinical significance of the disease, and such an overestimation may cause some confusion concerning the data on the JAK2 V617F mutation.…”

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confidence: 75%

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Chromosomal aberrations in leukaemia cells may delete tumour target antigens of stem cell-based immunotherapy

et al. 2006

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confidence: 62%

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confidence: 69%

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confidence: 75%

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Chromosomal aberrations in leukaemia cells may delete tumour target antigens of stem cell-based immunotherapy

et al. 2006

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“…The outcomes in our ALL study reported here, however, were poorer, especially for DFS. The poor GVL effect of DLI in ALL may be explained by the diverse immune escape mechanisms of leukemic cells, including the downregulation of HLA molecules, 23 defects in presentation of antigenic peptides, 24 deficient expression of costimulatory molecules, 25,26 induction of T-cell anergy to alloantigen, 26 secretion by leukemic cells of cytokines that inhibit activated lymphocytes, 27 and FAS ligand expression by leukemic cells. 28 However, it remains unclear why the GVL effect of DLI in ALL is weaker than that in myeloid leukemias, although it has been suggested that the better response of myeloid leukemia to DLI, compared with lymphoid leukemia, may be due to the direct presentation of leukemia antigens to donor T cells by myeloid leukemia-derived dendritic cells.…”

Section: Discussionmentioning

confidence: 99%

“…In the Japanese registry study, DLI alone induced CR in six of 24 patients, but only one patient maintained CR for 1 year. 22 The limited efficacy of DLI alone for relapsed ALL may be due in part to the diverse immune escape mechanisms of leukemic cells from GVL, [23][24][25][26][27][28] or to the rapid proliferation rate of leukemic cells coupled with the high-leukemic cell burden at the time of relapse, thus preventing the development of a clinically evident GVL effect. Since a GVL effect of DLI typically requires several weeks or months to become clinically apparent, 10,29,30 it would be reasonable to attempt cytoreductive chemotherapy before DLI in patients with rapidly advancing diseases such as ALL, thus allowing sufficient time for the development of the GVL effect.…”

Section: Geneic Bmt; Donor Leukocyte Infusionmentioning

confidence: 99%

Treatment of relapsed acute lymphoblastic leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a prospective study

Choi

Lee

Kim

et al. 2005

Bone Marrow Transplant

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Summary:Donor leukocyte infusion (DLI) alone has very limited efficacy for patients with acute lymphoblastic leukemia (ALL) who have relapsed after allogeneic bone marrow transplantation (BMT). We, therefore, prospectively tested the efficacy of cytoreductive chemotherapy (intermediate-dose cytarabine þ idarubicin þ etoposide) followed immediately by G-CSF-primed DLI (Chemo-DLI) in 10 relapsed ALL patients after allogeneic BMT. Seven achieved complete remission (CR) at a median of 25 days (19-73 days) after DLI. Of these seven CR patients, only one remains alive in CR 907 days after DLI. Two CR patients died in CR of graft-versus-host disease. The remaining four CR patients relapsed at a median of 153 days (120-991 days) after DLI. One is alive with leukemia at post-DLI day 1217. The median survival duration after DLI was 175 days (15-1217 days). In summary, although Chemo-DLI for relapsed ALL after allogeneic BMT induced a relatively high CR rate, durable remissions were rare. Although our data should be interpreted cautiously considering the small number of patients, these results suggest that poor outcome of DLI in relapsed ALL may be primarily due to intrinsic resistance to graft-versus-leukemia effect rather than to the rapid pace of the disease. For patients with acute lymphoblastic leukemia (ALL) receiving allogeneic bone marrow transplantation (BMT), relapse remains the major cause of treatment failure and is associated with a very poor prognosis. The optimal salvage treatment for patients with ALL who relapse after allogeneic BMT has not yet been established, since most therapies are of limited benefit. While reinduction chemotherapy can induce remission in about 40-60% of patients, most of these patients eventually relapse and die of uncontrolled leukemia, with a 3-year disease-free survival (DFS) rate of less than 10%. 1-4 A second BMT results in long-term event-free survival in only 10-20% of patients with relapsed ALL. 5-7 However, even these poor results may be an overestimate because only a small proportion of relapsed patients is suitable for second BMT, and hence the results may reflect the positively biased outcome of a highly selected group of patients. Only 7-20% of patients has been reported to reach the stage of a second BMT after relapse according to the performance and remission status after salvage chemotherapy. 2,8 Moreover, second BMT is associated with extremely high treatment-related mortality, ranging from 40% to 50%. [6][7][8] Another approach to the treatment of ALL patients who relapse after allogeneic BMT is donor leukocyte infusion (DLI), which may induce a graft-versus-leukemia (GVL) effect. DLI has been shown to be highly effective in patients with chronic myelogenous leukemia (CML) who relapse into the chronic phase, achieving complete and durable remission in 70-80% of these patients. 9,10 In contrast, DLI for relapsed ALL has been much less effective. Although there have been many case reports showing that patients with ALL respond to DLI, [11][12][13][14][15][16][17][18][...

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5′ and 3′ untranslated regions contribute to the differential expression of specific HLA‐A alleles

et al. 2015

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In hematopoietic stem cell transplantation (HSCT), when no HLA full-matched donor is available, alternative donors could include one HLA-mismatched donor. Recently, the low expressed HLA-C alleles have been identified as permissive mismatches for the best donor choice. Concerning HLA-A, the degree of variability of expression is poorly understood. Here, we evaluated HLA-A expression in healthy individuals carrying HLA-A*02 allele in different genotypes using flow cytometry and allele-specific quantitative RT-PCR. While an interindividual variability of HLA-A*02 cell surface expression, not due to the allele associated, was observed, no difference of the mRNA expression level was shown, suggesting the involvement of the posttranscriptional regulation. The results of qRT-PCR analyses exhibit a differential expression of HLA-A alleles with HLA-A*02 as the strongest expressed allele independently of the second allele. The associated non-HLA-A*02 alleles were differentially expressed, particularly the HLA-A*31 and HLA-A*33 alleles (strong expression) and the HLA-A*29 (low expression). The presence of specific polymorphisms in the 5 and 3 untranslated regions of the HLA-A*31 and HLA-A*33 alleles could contribute to this high level of expression. As previously described for HLA-C, low-expressed HLA-A alleles, such as HLA-A*29, could be considered as a permissive mismatch, although this needs to be confirmed by clinical studies.Keywords: Allele · Expression · HLA · Hematopoietic stem cell transplantation · Polymorphism Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHematopoietic stem cell transplantation (HSCT) is now widely used for the treatment of high-risk hematological malignancies, such as acute leukemia. To find a suitable donor, human leukocyte antigen (HLA) typing is performed. In most transplant Correspondence: Dr. Céline René e-mail: celine.rene@inserm.fr centers, a perfect match (10/10) of the ten alleles of the HLA-A, -B, -C, -DQB1, and -DRB1 loci is considered to be the optimal condition for HSCT with unrelated living donors. However, this requirement is fulfilled in just about half of the HSCTs, despite the expansion of international donor registries [1]. For patients lacking HLA-matched unrelated donors, single HLA * These authors contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2015. 45: 3454-3463 Molecular immunology 3455 mismatch unrelated donors might be considered as alternative donors. However, the risk of graft versus host disease (GVHD) is increased and overall survival is reduced in patients who receive a graft from a donor with a single mismatch in the HLA class I locus compared with the HLA-matched situation [2,3]. Moreover, the adverse effects on the patient's outcome depend also on the locus carrying the mismatch between donor and recipient [4,5]. In this context, in order to increase the safety of HSCT with HLA-mismatched unrelated donors, a better understanding of the factors that trigger t...

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Loss or downregulation of HLA class I expression at the allelic level in acute leukemia is infrequent but functionally relevant, and can be restored by interferon

Cited by 73 publications

References 28 publications

Chromosomal aberrations in leukaemia cells may delete tumour target antigens of stem cell-based immunotherapy

Chromosomal aberrations in leukaemia cells may delete tumour target antigens of stem cell-based immunotherapy

Treatment of relapsed acute lymphoblastic leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a prospective study

5′ and 3′ untranslated regions contribute to the differential expression of specific HLA‐A alleles

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