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.

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

Occurrence and Impact of Minor Histocompatibility Antigens' Disparities on Outcomes of Hematopoietic Stem Cell Transplantation from HLA-Matched Sibling Donors

“…Amino-acid polymorphism may be present in the region of MiHA that binds to HLA molecule, causing different expressions of peptide-HLA complex in the donor than in the recipient. Polymorphism may also pertain proteins responsible for intracellular processing of peptides, what leads to the presence or absence of peptides (e.g., HA-2 or HA-8) on cell's surface [ 12 ], or phosphoproteins (e.g., SP-110, MiHA discovered in 2006 by Warren et al) [ 13 ].…”

“…Most MiHA possess only one immunogenic allele, which is sufficient to induce MiHA immunogenicity [ 12 ]. Up to date 18 autosomal and 10 Y-chromosome encoded MiHAs have been identified; those tested in our study are presented in Tables 1 and 2 .…”

“…There are two patterns of MiHAs' tissue distribution: restricted and broad. Autosomal HA-3, HA-8, and most of MiHAs encoded by Y-chromosome are present in most tissues, including those crucial for GVHD: skin, intestines, and liver [ 11 , 12 ]. Most of autosomal and 2 MiHAs encoded by Y-chromosome (B8/HY and B52/HY) appear only in hematologic cells including leukemic cells, dendritic cells, NK, and multiple myeloma cells [ 40 ].…”

“…Female recipients after transplantation from male donors may experience graft failure due to HVG reaction against HY antigens resulting in a worse survival [ 3 ]. MiHA present on recipient's neoplasmatic cells (HA-1, HA-2, HA-8, HB-1, and HY) may constitute the target of cytotoxic CD8+ T-lymphocytes crucial for GVL reaction [ 12 , 50 ], leading to the decrease of relapse rate [ 51 ]. Use of cytotoxic T-lymphocytes recognizing selectively only MiHA present on neoplasmatic cells enables the separation of GVL effect from GVHD [ 52 ].…”

“…Such MiHAs can be used both in vivo for the production of vaccines enhancing GVL reaction and in vitro as a load to antigen presenting cells stimulating reactivity of cytotoxic T-cells [ 53 ]. HA-1 and HA-2 are the most intensively explored MiHAs in immunotherapy [ 12 , 52 – 54 ].…”