Proteogenomic-based discovery of minor histocompatibility antigens with suitable features for immunotherapy of hematologic cancers (original) (raw)
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miHA-Match: Computational detection of tissue-specific minor histocompatibility antigens
Journal of Immunological Methods, 2012
Allogenic stem cell transplantation has shown considerable success in a number of hematological malignancies, in particular in leukemia. The beneficial effect is mediated by donor T cells recognizing patient-specific HLA-binding peptides. These peptides are called minor histocompatibility antigens (miHAs) and are typically caused by single nucleotide polymorphisms. Tissue-specific miHAs have successfully been used in anti-tumor therapy without causing unspecific graft-versus-host reactions. However, only a small number of miHAs have been identified to date, limiting the clinical use.
Computational modeling and confirmation of leukemia-associated minor histocompatibility antigens
Blood advances, 2018
T-cell responses to minor histocompatibility antigens (mHAs) mediate both antitumor immunity (graft-versus-leukemia [GVL]) and graft-versus-host disease (GVHD) in allogeneic stem cell transplant. Identifying mHAs with high allele frequency, tight binding affinity to common HLA molecules, and narrow tissue restriction could enhance immunotherapy against leukemia. Genotyping and HLA allele data from 101 HLA-matched donor-recipient pairs (DRPs) were computationally analyzed to predict both class I and class II mHAs likely to induce either GVL or GVHD. Roughly twice as many mHAs were predicted in HLA-matched unrelated donor (MUD) stem cell transplantation (SCT) compared with HLA-matched related transplants, an expected result given greater genetic disparity in MUD SCT. Computational analysis predicted 14 of 18 previously identified mHAs, with 2 minor antigen mismatches not being contained in the patient cohort, 1 missed mHA resulting from a noncanonical translation of the peptide antige...
Tissue …, 2010
CITATIONS 5 READS 125 26 authors, including: Some of the authors of this publication are also working on these related projects: Hematological and Solid Tumors: from biomolecular characterization to development of new personalized therapeutic strategies View project Transplantation and oncology: genetic analysis of immunological biomarkers involved in tolerance and tumor pathogenesis. View project Abstract During the 15th International Histocompatibility and Immunogenetics Workshop (IHIWS), 14 human leukocyte antigen (HLA) laboratories participated in the Analysis of HLA Population Data (AHPD) project where 18 new population samples were analyzed statistically and compared with data available from previous workshops.
Determinants recognized by human cytotoxic T cells on a natural hybrid class I HLA molecule
Journal of Experimental Medicine, 1985
The major histocompatibility complex (MHC) class I molecules are the primary determinants recognized by allogeneic cytotoxic T lymphocytes (CTL), and serve as restricting elements for CTL recognition of viral, chemical, or minor histocompatibility antigens (1). Our understanding of the manner in which these molecules participate in immune responses has been significantly advanced by the development of techniques for expressing MHC genes following DNAmediated transfer into suitable recipient cells (2-4). More recently, transfections have been undertaken with genes that have been manipulated in vitro to produce novel structures. Results from such studies have shown that the major determinants recognized by murine CTL lie in the highly polymorphic oq and/or 0/2 domains (5-9). However, similar analyses of human CTL recognition of transfected HLA molecules have been more difficult to interpret. A number of investigators (i 0, 1 I) have shown that human HLA-A2 and-B7 genes transfected into murine L cells are not recognized by human allogeneic CTL, suggesting that species-restricted factors may play a role in the cellular but not serological recognition of human MHC class I molecules. In contrast, others have reported (12, 13) that HLA-A3 and-Aw24 transfected into and expressed by murine L cells can be recognized by human CTL. Thus, it appears that properties of the recipient cell and/or a particular HLA molecule can affect the ability of human CTL to recognize transfected HLA genes. We have previously shown (14) 1 that HLA-Aw69 is a naturally occuring hybrid class I molecule, in that the al domain is identical to that of HLA-Aw68, and the a2 and a3 domains are identical to those of HLA-A2. To localize the functional determinants recognized by human allogeneic CTL, we used human B iymphoblastoid cell lines, which normally express these HLA molecules, as stimulators to generate CTL clones, and as targets to assess CTL specificity. We show here that human CTL clones can recognize determinants in either the 0/1 or ol 2 domains, and that interaction of the 0/1 and 0/2 domains can result in the formation of determinants or the loss of preexisting determinants. Materials and Methods Cell Lines. CTL clones were generated as described previously (15, 16). Briefly, peripheral blood lymphocytes from a normal donor (HLA-A3,-; B7,w38; C- ,-; DR6,6) i N. Holmes and P. Parham. Exon shuffling in vivo can generate novel HLA class 1 molecules.
Tissue Antigens, 2007
The application of peptide-based immunotherapy in the treatment of cancer has known limitations in patients with loss or downregulation of human leukocyte antigen (HLA) class I expression on tumor cells. These alterations diminish the ability of cancer cells to present tumor peptides to T cells and therefore lead to failure of peptide-based cancer vaccination. Abnormal expression of HLA class I molecules in malignant cells is a frequent event that ranges from total loss of class I molecules to partial loss of HLA-specific haplotypes or alleles. Different mechanisms underlie these alterations and might require different therapeutic approaches. A complete characterization of molecular defects may suggest strategies for the selection and follow-up of patients undergoing T-cell based immunotherapy. Moreover, a precise identification of the mechanism leading to HLA class I defects in patients with cancer will help develop new, personalized patient-tailored treatment protocols. Here, we describe several examples showing the necessity and feasibility of making detailed individual analysis of HLA alteration mechanisms based on previously described molecular patterns in different types of malignancy. We recommend using this approach, at least in some patients, to enhance the therapeutic benefit of cancer immunotherapy.