title: Therapeutic and diagnostic applications of minor histocompatibility antigen HA-1 and HA-2 disparities in allogeneic hematopoietic stem cell transplantation: a survey of different populations.
abstract: Minor histocompatibility antigens (mHags) HA-1 and HA-2 are encoded by biallelic loci, with immunogenic variants, HA-1H and HA-2V, which induce strong HLA-A2-restricted alloreactive T-cell responses, and nonimmunogenic counterparts, HA-1R and HA-2M, which represent functional null alleles that are poorly presented by HLA class I molecules. HA-1 and HA-2 are potential targets of selective graft-versus-leukemia and graft-versus-tumor reactivity after allogeneic hematopoietic stem cell transplantation (HSCT); however, these applications are restricted to a limited number of patients. Here, we show that a far more frequent application of HA-1 and HA-2 disparity relies on their use as markers for the state of host chimerism after allogeneic HSCT. We have determined allelic frequencies of 29.3% and 70.7% for HA-1H and HA-1R, respectively, and of 83.7% and 16.3% for HA-2V and HA-2M, respectively, in >200 healthy individuals from northern Italy. Similar frequencies were observed in nearly 100 patients affected by hematologic malignancies or solid tumors, thus showing that HA-1 and HA-2 variability are not associated with the presence of cancer. On the basis of these data, we predict that HA-1 and HA-2 can be used in 32.8% and 23.5% of Italian transplant patients, respectively, as markers for the state of host chimerism, whereas exploitation of disparity for these mHags for targeted immunotherapy will be possible in 10.7% and 1.1% of Italian patients, respectively. Retrospective HA-2 typing of bone marrow aspirates obtained from a patient during complete remission or recurrence of acute myeloid leukemia after haploidentical HSCT showed the feasibility of using HA-2 as a surrogate marker for disease monitoring. Because of an apparent north-south gradient for HA-1 allelic frequencies, with higher frequencies for the HA-1H variant reported in white populations from Southern Europe as compared with Northern Europe and North America, the diagnostic applicability of HA-1 disparity will be slightly more frequent in transplant patients from the north. Taken together, our data show that determination of HA-1 and HA-2 variability can be an important parameter for the selection of allogeneic stem cell donors, in particular for patients affected by hematologic malignancies without a tumor-specific molecular marker.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, IRCCS Istituto Scientifico H.S. Raffaele, Milan, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Di Terlizzi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Zino
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mazzi
authors.forename: Chiara
authors.initials: C
authors.lastname: Magnani
authors.forename: Cristina
authors.initials: C
authors.lastname: Tresoldi
authors.forename: Serena Kimi
authors.initials: SK
authors.lastname: Perna
authors.forename: Marco
authors.initials: M
authors.lastname: Bregni
authors.forename: Silvano
authors.initials: S
authors.lastname: Rossini
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Chiara
authors.initials: C
authors.lastname: Bonini
authors.forename: Katharina
authors.initials: K
authors.lastname: Fleischhauer
mesh_terms: D015415:Biomarkers / Q000032:analysis; D005787:Gene Frequency; D019337:Hematologic Neoplasms / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006650:Histocompatibility Testing / Q000379:methods*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D007951:Leukemia, Myeloid / Q000175:diagnosis / Q000276:immunology; D015778:Minor Histocompatibility Antigens / Q000032:analysis* / Q000235:genetics; D017720:Molecular Epidemiology; D009363:Neoplasm Proteins / Q000032:analysis* / Q000235:genetics; D009842:Oligopeptides / Q000032:analysis* / Q000235:genetics; D014019:Tissue Donors; D018183:Transplantation Chimera; D014184:Transplantation, Homologous
chemical_list: D015415:Biomarkers; C110615:HA-1 antigen; C080145:HA-2 antigen; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; D009842:Oligopeptides