Y-Chromosome Genes Strongly Expressed in Acute Myeloid Leukaemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4901-4901
Author(s):  
Antonio Gallo ◽  
Dagmar Bund ◽  
Rebecca Mindnich ◽  
Raymund Buhmann ◽  
Helga Schmetzer ◽  
...  
Keyword(s):  
Binding Capacity ◽  
Graft Versus Host Reaction ◽  
Immune Recognition ◽  
Hematopoietic Stem ◽  
Substantial Impact ◽  
Minor Histocompatibility Antigens ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
293 Cells ◽  
Proteasomal Cleavage

Abstract In hematopoietic stem cell transplantation (HSCT) the gender of the donors has a substantial impact on the relapse rate, graft-versus-host reaction and overall therapeutic outcome. In several studies including our own HLA-haploidentical setting female to male transplantation seemed to be superior to other gender combinations, suggesting the dominance of Y-encoded minor histocompatibility antigens for graft-versus-leukemia reactions. In order to explore the therapeutic possibilities we compared the Y-chromosomal gene expression between isolated AML blasts (FAB M4/M5) and isolated CD14+ cells from healthy male donors. RNA was isolated and subsequently analyzed by low density arrays (LDAs), a real time-PCR based method. This way we could identify four Y-encoded genes found to be strongly up-regulated in the AML samples. Bcorl2, a pseudogene; pcdh11y, known to be involved in acquisition of apoptotic resistance in prostate cancer; tgif2ly and vcy, both putative transcription factors. The genes were cloned in plasmids and transferred in 293 cells. The expression of these proteins was analyzed by western blot. Biostatistical soft ware was used to predict the proteasomal cleavage site and binding capacity to HLA-A 0201 of these peptides. Five peptides were found to bind strongly to HLA-A 0201; they are now studied for recognition by female T cells. In summary, the genes identified might be involved in the immune recognition of AML blasts and other tumor cells. These peptides may help to identify and select T memory cells specific for AML blasts.

Graft-versus-leukemia effect after suicide-gene–mediated control of graft-versus-host disease

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2020-2025 ◽  
Author(s):  
Elena Litvinova ◽  
Sébastien Maury ◽  
Olivier Boyer ◽  
Sylvie Bruel ◽  
Laurent Benard ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Therapeutic Strategy ◽  
Suicide Gene ◽  
Graft Versus Host Reaction ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Dividing Cells

Abstract Clinical data indicate that after allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies, the graft-versus-leukemia (GVL) effect is in large part mediated by the graft-versus-host reaction (GVHR), which also often leads to graft-versus-host disease (GVHD). Controlling alloreactivity to prevent GVHD while retaining GVL poses a true dilemma for the successful treatment of such malignancies. We reasoned that suicide gene therapy, which kills dividing cells expressing the thymidine kinase (TK) “suicide” gene using time-controlled administration of ganciclovir (GCV), might solve this dilemma. We have previously shown that after infusion of allogeneic TK T cells along with HSCT to an irradiated recipient, an early and short GCV treatment efficiently prevents GVHD by selectively eliminating alloreactive T cells while sparing nonalloreactive T cells, which can then contribute to immune reconstitution. Nevertheless, it remained to be established that this therapeutic strategy retained the desired GVL effect. Hypothesizing that a contained GVHR would be essential, we evaluated the GVL effect using different protocols of GCV administration. We were able to show that when the GCV treatment is initiated at, or close to, the time of grafting, GVHD is controlled but GVL is lost. In contrast, when the onset of GCV administration is delayed until day 6, a potent GVL effect is retained while GVHD is still controlled. These data emphasize that, by a time-optimized scheduling of the administration of GCV, this TK/GCV strategy can be tuned to efficiently treat malignant hemopathies.

scholarly journals Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Makoto Nakamura ◽  
Yusuke Meguri ◽  
Shuntaro Ikegawa ◽  
Takumi Kondo ◽  
Yuichi Sumii ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell Subsets ◽  
Inkt Cells ◽  
Early Recovery ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Reduced Dose ◽  
Graft Versus Leukemia ◽  
Novel Strategy

AbstractPosttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient’s condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by α-galactosylceramide (α-GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of α-GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4+Foxp3+ regulatory T cells. These studies indicate that α-GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk.

scholarly journals Characterisation of B killer cell immunoglobulin-like receptor genes and telomeric and centromeric motifs in hematopoietic stem cell transplantation donors in Vojvodina, Serbia

Genetika ◽  
2017 ◽  
Vol 49 (1) ◽  
pp. 345-354
Author(s):  
Dusica Ademovic-Sazdanic ◽  
Svetlana Vojvodic ◽  
S. Popovic ◽  
N. Konstantinidis
Keyword(s):  
Relapse Prevention ◽  
Hematological Malignancies ◽  
Killer Cell ◽  
Simple Algorithm ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Kir Genes ◽  
Graft Versus Leukemia ◽  
Kir Gene ◽  
Kir Genotypes

The outcome of HSCT is strongly in?uenced by the genetic similarity or identity in the HLA genes that affects the incidence of graft-versus-host disease (GvHD). Successful allogeneic HSCT, however, depends also on T-cell mediated graft-versus-leukemia (GvL) effect, in which donor-derived T cells and natural killer (NK) cells kill these malignant cells in the patient, therefore playing a crucial role in relapse prevention. The aim of this study was to make the predictive analysis of the structure and distribution of B KIR alleles and centromeric and telomeric KIR genotypes in HSCT donors in Vojvodina with regard to their contribution to protection from relapse. A total of 124 first-degree relatives of patients with hematological malignancies were examined for the presence or absence of 15 KIR genes by using of PCR-SSO technique with Luminex xMap technology. The percentage of individuals carrying each KIR gene, centromeric and telomeric KIR haplotypes and genotypes was determined by direct counting. Sixty two percent of the HSCT donors in Vojvodina carry A KIR haplotype, while nearly 38% carry B KIR haplotype. The distribution of B KIR genes showed that among 124 studied HSCT donors, 31(25%) do not carry none of the KIR genes belonging to B group, 71.77% of donors have two or more B KIR genes, 61.29% of them carry KIR 2DL2 and 2DS2 or more B KIR genes. The analysis of centromeric and telomeric KIR genotypes, showed that Cen-A1/Tel-A1 genotype had a highest frequency of 51.47% and Cen-B2/Tel-B1 the lowest frequency of 1.30%. The usage of donor KIR B gene content and centromeric and telomeric KIR gene structure could be used in development of a simple algorithm to identify donors who will provide the most protection against the relapse in related HSC transplants.

Beyond HLA: Impact of Immunoreactive Mismatches of Minor Histocompatibility Antigens on Probability of Relapse and Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation from HLA-Matched Unrelated Donors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3156-3156
Author(s):  
Miroslaw Markiewicz ◽  
Urszula Siekiera ◽  
Jerzy Wojnar ◽  
Agata Wieczorkiewicz ◽  
Iwona Wylezol ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Standard Operating Procedure ◽  
Host Responses ◽  
Histocompatibility Antigens ◽  
Hematopoietic Stem ◽  
Minor Histocompatibility Antigens ◽  
Graft Versus Host ◽  
Probability Of Survival ◽  
Unrelated Donors

Abstract Factors contributing to relapses and GVHD following allogeneic Hematopoietic Stem Cell Transplantations (HSCT) from HLA-matched unrelated donors are not well established. We analyzed 35 patients (pts) transplanted from HLA 10/10 alleles (A, B, C, DRB1, DQB1) matched unrelated donors (URD) in the Dept. of Hematology and BMT, Katowice, Poland, with use of the same standard operating procedure from January 2004 until March 2006. Indication for HSCT was AML (13 pts), ALL (8), CML (7), MDS (2), PNH (3), CLL (1), myeloid sarcoma (1). Preparative regimen was Treosulfan+Fludarabine (23 pts), TBI+Cy (9) and Bu+Cy (3). Alleles encoding 11 minor Histocompatibility Antigens (mHA: HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, HwA-9, HwA-10, UGT2B17, HY) were analyzed for each donor-recipient pair with use of Dynal AllSet mHA typing kit and PCR-SSP method. Only immunogenic mHA mismatches were analyzed. Information on whether mHA mismatches might result in Host-versus-Graft or Graft-versus-Host responses was established with use of the minor Histocompatibility Knowledge Database of Leiden University Medical Center’s minor Histocompatibility Workshop. Patients transplanted from donors with mHA mismatched in HVG direction had significantly higher probability of relapse (64+/− 8% versus 10+/− 9%, p=0.003) when compared to pairs without mHA HVG immonogenicity. Patients transplanted from donors with mHA mismatched in GVH direction had higher probability of aGVHD (88+/− 8% versus 53+/− 11%, p=0.14) and cGVHD (41+/− 16% versus 37+/− 17%, p=0.65) when compared to pairs without GVH immunogenicity. GVHD was also observed more often on day +100 (33% versus 6%, p=0.06) when mHA mismatch in GVH direction was present. Observed influence of HVG and GVH immonogenicity on probability of relapse and GVHD did not lead to significantly different survival in observed groups of pts. These results indicate that mHA immunogenic mismatches in HVG and GVH direction may be responsible for relapse and GVHD, respectively, in HSCT recipients from HLA-matched unrelated donors. The study is being continued to confirm these primary observations and to establish the associations of specific mHA mismatches with HSCT outcomes. Impact of mHA mismatch on probability of relapse and GVHD Immunogenicity of mHA mismatches HVG no HVG p # of patients 18 17 Relapse at 1 year 64%+/−8 10%+/−9 0.003 Immunogenicity of mHA mismatches GVH no GVH p # of patients 16 19 aGVHD 88%+/− 8 53%+/−11 0.14 cGVHD at 1 year 41%+/−16 37%+/−17 0.65 Impact of mHA mismatch on probability of survival Immunogenicity of mHA mismatches HVG GVH only HVG only GVH no HVG no GVH p # of patients 9 9 7 10 Survival at 9 months 63%+/−17 57%+/−25 83%+/−15 69%+/−15 0.86

Genome Wide Single Nucleotide Polymorphism Typing for Identification of Putative Minor Histocompatibility Antigens in Graft Versus Host Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 447-447 ◽  
Author(s):  
Ann Mullally ◽  
Cheng Li ◽  
Haesook Kim ◽  
Mehrdad Mohseni ◽  
Edwin P. Alyea ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Histocompatibility Antigens ◽  
Single Nucleotide ◽  
Hematopoietic Stem ◽  
Minor Histocompatibility Antigens ◽  
Sibling Pairs ◽  
Graft Versus Host ◽  
Genome Wide

Abstract Previous studies have demonstrated that disparity across minor histocompatibility antigens (mHA) can cause graft versus host disease (GVHD) in patients who receive hematopoietic stem cell grafts from HLA-identical donors. mHA are peptide epitopes derived from normal cellular proteins presented by self MHC. Most autosomal mHA are generated as a result of non-synonymous coding single nucleotide polymorphisms (cSNPs), which lead to differences in the amino acid sequences of homologous proteins between donor and recipient cells. Although it is estimated that several hundred mHA exist in humans, only 16 have been definitively characterized to date. Using the Affymetrix 20K cSNP array we performed SNP typing on 97, HLA-A2+ hematopoietic stem cell transplant (HSCT) recipients and their sibling donors. Genomic DNA was extracted from peripheral blood mononuclear cells (PBMC) obtained from patients and their donors. All patients were in remission at the time of sampling, all had undergone HSCT at the Dana-Farber Cancer Institute between 1998 and 2005 and all samples were drawn prior to transplantation. The transplants included myeloablative and non-myeloablative conditioning regimens, T cell depleted and non-T cell depleted grafts and sex matched and sex mis-matched donors. Using dChip software, we evaluated each of the 20,000 non-synonymous cSNPs on the array for mismatch between sibling pairs and for an association between mismatch in the GVHD direction and the development of acute or chronic GVHD. Mismatch in the GVHD direction was defined as a homozygous donor (AA or BB) and a heterozygote recipient (AB) or a homozygous donor (AA or BB) and a homozygously mismatched recipient (BB or AA). We ranked the cSNPs on the array in order of the strength of the association between mismatch in the GVHD direction and the development of either acute or chronic GVHD. There was no overlap between the 40 mismatched cSNPs most strongly associated with acute GVHD and the 40 most tightly associated with chronic GVHD. Mismatch at the SNP rs12407003 in the OMA1 gene was most highly associated with acute GVHD with mismatch in the GVHD direction occurring in 13 of 41 pairs with acute GVHD and 2 of 56 without (p=0.0003 by Fisher’s Exact Test). OMA1 encodes a mitochondrial membrane-bound metallopeptidase. 65 sibling pairs were assessable for chronic GVHD. Mismatch at the SNP rs2740349 in the GEMIN4 gene was most strongly associated with chronic GVHD with mismatch in the GVHD direction occurring in 10 of 26 pairs with chronic GVHD and 1 of 39 without (p=0.0002). GEMIN4 is part of a cytoplasmic multiprotein complex. This study demonstrates a novel, genome-wide method of identifying putative mHA using a cSNP array. It reveals that mismatch of non-synonymous cSNPs in the GVHD direction occurs at an appreciable frequency in sibling pairs consistent with the hypothesis that the number of mHA in humans is large. Interestingly, the pattern of mismatch differs between acute and chronic GVHD. The study also identifies individual non-synonymous cSNPs for which mismatch in the GVHD direction is highly associated with the development of GVHD. Further evaluation of these cSNPs in larger independent cohorts will be undertaken to validate this association and targeted immunologic analysis of peptides derived from these cSNPs will examine their role as putative mHA.

The role of B cells in the pathogenesis of graft-versus-host disease

Blood ◽  
2009 ◽  
Vol 114 (24) ◽  
pp. 4919-4927 ◽  
Author(s):  
Alexander Shimabukuro-Vornhagen ◽  
Michael J. Hallek ◽  
Rainer F. Storb ◽  
Michael S. von Bergwelt-Baildon
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
B Cells ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Chronic Gvhd ◽  
Graft Versus Host Reaction ◽  
Hematopoietic Stem ◽  
Graft Versus Host

Abstract Allogeneic hematopoietic stem cell transplantation is an established treatment modality for malignant and nonmalignant hematologic diseases. Acute and chronic graft-versus-host diseases (GVHDs) are a major cause of morbidity and mortality after allogeneic stem cell transplantation. T cells have been identified as key players in the graft-versus-host reaction and, therefore, most established drugs used against GVHD target T cells. Despite our knowledge on the pathogenesis of the GVH reaction, success of established therapies for prevention and treatment of GHVD is unsatisfactory. Recently, animal and human studies demonstrated that B cells are involved in the immunopathophysiology of acute and chronic GVHD. Early phase clinical trials of B-cell depletion with rituximab have shown beneficial effects on both acute and chronic GVHD. This review summarizes the current experimental and clinical evidence for the involvement of B cells in the pathogenesis of acute and chronic GVHD and discusses the clinical implications for the management of patients undergoing allogeneic stem cell transplantation.

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