Identification of 4 new HLA-DR–restricted minor histocompatibility antigens as hematopoietic targets in antitumor immunity

Stumpf, Alexia; Meijden, Edith D. van der; Bergen, Cornelis A.M. van; Willemze, R.; Falkenburg, J.H. Frederik; Griffioen, Marieke

doi:10.1182/blood-2009-03-208017

Cited by 62 publications

(66 citation statements)

References 51 publications

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“…[26][27][28] Hela cells retrovirally transduced with the invariant chain (Ii chain) and HLA-DM were previously generated. 28 HLA-DRB1*1301, 29 -DRB3*0101, 29 -DPB1*0101, 28 -DPB1*0301 7 and -DPB1*0401 30 were cloned into MP71-IRES-NGFR, whereas HLA-DQB1*0603 and HLA-DPA1*0201 28 were cloned into LZRS-IRES-GFP. 26 Transduced cells with HLA-class II genes were isolated based on marker gene expression (NGFR and/or GFP) by magnetic beads (PE-labeled human NGFR moAb (Cedarlane laboratories, Burlington, VT, USA) and anti-PE-coated magnetic beads (Miltenyi Biotec GmbH) or by flowcytometry based on co-expression of GFP and NGFR.…”

Section: Target Cells For Functional Studiesmentioning

confidence: 99%

Human allo-reactive CD4+ T cells as strong mediators of anti-tumor immunity in NOD/scid mice engrafted with human acute lymphoblastic leukemia

et al. 2011

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Adoptive immunotherapy with donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (alloSCT) may not only mediate Graft-versus-Leukemia (GvL) reactivity, but also induce Graft-versus-Host Disease (GvHD). As HLA-class II molecules are predominantly expressed on hematopoietic cells, CD4 þ T cells may selectively mediate GvL reactivity without GvHD. Here, we assessed the capacity of human CD4 þ T cells to act as sole mediators of GvL reactivity in a NOD/scid mouse model for human acute lymphoblastic leukemia and chronic myeloid leukemia in lymphoid blast crisis. Highly purified CD4 þ DLI eradicated the leukemic cells. The anti-tumor immunity was mediated by a polyclonal CD4 þ T cell response comprising cytokine-producing T-helper and cytolytic T-effector cells directed against the mismatched HLA-class II molecules of the patients. Furthermore, primary leukemic cells acquired an antigen-presenting cell (APC) phenotype in vivo after DLI, as well as in vitro after co-culture with leukemia-specific CD4 þ T cells. In conclusion, our results show that CD4 þ T cells can be strong mediators of anti-tumor immunity, and provide evidence that cross-talk between CD4 þ T cells and leukemic cells is the basis for induction of leukemic cells with an APC phenotype. These data emphasize the clinical relevance of CD4 þ T cell based immunotherapy as treatment modality for hematological malignancies after alloSCT.

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Section: Target Cells For Functional Studiesmentioning

confidence: 99%

Human allo-reactive CD4+ T cells as strong mediators of anti-tumor immunity in NOD/scid mice engrafted with human acute lymphoblastic leukemia

et al. 2011

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“…Most of these are HLA class I-restricted (18), and only two, DDX3Y and RPS4Y, encode HLA class II-restricted male-specific minor H Ags (6,7,19). To date, very few peptide epitopes have been characterized (20)(21)(22)(23).…”

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confidence: 99%

Isolation of Human CD4/CD8 Double-Positive, Graft-Versus-Host Disease–Protective, Minor Histocompatibility Antigen–Specific Regulatory T Cells and of a Novel HLA-DR7–Restricted HY-Specific CD4 Clone

Eljaafari

Yuruker

Ferrand

et al. 2013

The Journal of Immunology

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Minor histocompatibility (H) Ags are classically described as self-peptides derived from intracellular proteins that are expressed at the cell surface by MHC class I and class II molecules and that induce T cell alloresponses. We have isolated three different T cell populations from a skin biopsy of a patient suffering from acute graft-versus-host disease following sex-mismatched HLA-identical bone marrow transplantation. The first population was: 1) CD4+/CD8+ double-positive; 2) specific for an HLA class I–restricted autosomal Ag; 3) expressed a Tr1 profile with high levels of IL-10, but low IL-2 and IFN-γ; and 4) exerted regulatory function in the presence of recipient APCs. The second was CD8 positive, specific for an HLA class I–restricted autosomally encoded minor H Ag, but was only weakly cytotoxic. The third was CD4 single positive, specific for an HLA-DR7–restricted HY epitope and exerted both proliferative and cytotoxic functions. Identification of the peptide recognized by these latter cells revealed a new human HY epitope, TGKIINFIKFDTGNL, encoded by RPS4Y and restricted by HLA-DR7. In this paper, we show human CD4/CD8 double-positive, acute graft-versus-host disease–protective, minor H Ag–specific regulatory T cells and identify a novel HLA-DR7/ HY T cell epitope, encoded by RPS4Y, a potential new therapeutic target.

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“…19 The specificity of this T-cell clone was demonstrated by IFN-γ production upon stimulation with patient, but not donor, EBV-LCL as well as donor EBV-LCL loaded with LB-PTK2B-1T peptide ( Figure 1A). To investigate in vivo dynamics of the T-cell response, we developed a clonotypic PCR for the CDR3 region of clone 78 and detected a specific PCR product in patient PBMC 9 weeks after DLI (Ct = 36), but not in patient samples collected before alloSCT or prior to DLI and in a donor sample, whereas the PBGD housekeeping gene was similarly expressed in all samples (Ct = 25-27) (data not shown).…”

Section: Lb-ptk2b-1t Specific Cd4 + T Cells Can Provide Specific Helpmentioning

confidence: 99%

Development of a coordinated allo T cell and auto B cell response against autosomal PTK2B after allogeneic hematopoietic stem cell transplantation

et al. 2013

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+T-cell and auto-reactive antibody response against an autosomal antigen. ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nThis antibody response was mapped to a small nonpolymorphic region of the protein. In conclusion, this is the first report demonstrating induction of a coordinated allo-T cell and auto-B cell response against an autosomal antigen after alloSCT. Methods Hematopoietic samplesPeripheral blood and bone marrow samples were obtained from patients and healthy individuals after approval by the Leiden University Medical Center Institutional Review Board and informed consent according to the Declaration of Helsinki. Antigen presentation assaysEBV-LCL were loaded with 1 mg/mL of synthetic peptides in IMDM with 2% FCS and incubated for 2 h at 37°C. Cells were washed twice and plated at 30,000 cells/well in a 96-well plate. Effector cells were added at 5000 T cells/well. After overnight coincubation, IFN-γ production was measured by ELISA (Sanquin, Burton upon Trent, UK) according to the manufacturer's instructions. Helper function assaysTo induce maturation of dendritic cells (DC), CD4 + T-cell clones and immature DC were seeded in a 1:1 ratio in a 24-well plate. After four days of co-incubation, cells were harvested, washed and stained with antibodies for FACS analysis. For induction of B-cell activation, CD4 + T-cell clones and isolated B cells were seeded in a 1:1 ratio and after two days of co-incubation, cells were harvested, washed and stained for FACS analysis. Western blot analysisWhole cell lysates of transfected HEK293T cells were obtained from OriGene (Rockville, USA). HeLa cells were retrovirally transduced with MP71 vector containing PTK2B or PI4K2B constructs; 20 mg of protein was loaded on each lane. SDS-Page was run on pre-cast NuPage® Novex 10% Bis-Tris Mini gels (Invitrogen) for 35 min at 30V under reducing conditions. Gels were blotted on PVDF membranes using XCell SureLock® Mini-Cell blotting system (Invitrogen) according to the manufacturer's instructions. Blots were blocked for 1 h at room temperature in phosphatebuffered saline with 0.05% Tween-20 and 5% BSA, and subsequently incubated with diluted (1:40) serum samples overnight at 4°C. Subsequently, the membrane was incubated with biotinylated anti-human IgG and streptavidin-QDots 625 (Invitrogen) for 1 h each and visualized under UV illumination. Suspension bead arrayThe suspension bead array was performed as previously described. 20,21 Purified proteins (20 mg) were coupled to carboxylated beads (Bio-Rad Laboratories B.V.) according to the manufacturers' instructions. Diluted serum samples (1:100 and 1:300) were pre-absorbed with 0.5% (w/v) polyvinylalcohol and 0.8% (w/v) polyvinylpyrrolidone (Sigma) (PVX) and 1% bovine serum albumin (BSA) for 1 h prior to incubation with the protein-coupled bead mix at room temperature on a shaker for 1 h. In specific blocking experiments, serum samples were pre-absorbed with purified recombinant proteins at 0.5 or 2.0 mg/mL in PVX and 1% BSA. Beads were washed and incubated for another...

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Identification of 4 new HLA-DR–restricted minor histocompatibility antigens as hematopoietic targets in antitumor immunity

Cited by 62 publications

References 51 publications

Human allo-reactive CD4+ T cells as strong mediators of anti-tumor immunity in NOD/scid mice engrafted with human acute lymphoblastic leukemia

Human allo-reactive CD4+ T cells as strong mediators of anti-tumor immunity in NOD/scid mice engrafted with human acute lymphoblastic leukemia

Isolation of Human CD4/CD8 Double-Positive, Graft-Versus-Host Disease–Protective, Minor Histocompatibility Antigen–Specific Regulatory T Cells and of a Novel HLA-DR7–Restricted HY-Specific CD4 Clone

Development of a coordinated allo T cell and auto B cell response against autosomal PTK2B after allogeneic hematopoietic stem cell transplantation

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