Impact of Homozygous Conserved Extended HLA Haplotypes on Cord Blood Transplantation: Implications for Induced Pluripotent Stem Cell Banking and Transplantation
Authors: Morishima Yasuo , Morishima Satoko , Murata Makoto , Arima Nobuyoshi , Uchida Naoyuki , Ohno Yuji , Takahashi Satoshi , Matsuhashi Yoshiko , Onizuka Makoto , Eto Tetsuya , Atsuta Yoshiko , Fukuda Takahiro , Ichinohe Tatsuo , Kato Shunichi , Kanda Junya 
Published: October 2019

Abstract
Induced pluripotent stem cells (iPSC) have the capacity to generate various tissues/organs, and clinical application in autologous settingsin humans has just begun. However, autologous transplantation is hampered by the high time and cost required for the individual production of iPSC. To solve these issues, allogeneic iPSC transplantation (allo-iPS-T) from iPSC banking has been proposed. A candidate for this is iPSC induced from individuals with a homozygous HLA haplotype (HLA-homo), on the basis that HLA-homo iPSC might not be rejected by HLA haplotype-matched patients. Concerns have been raised over whether allo-iPS-T from HLA-homo iPSC induces immunogenicity in clinical settings. Cord blood transplantation (CBT) might be a suitable model for evaluating these concerns, because HLA mismatch CBT from donors with less than two HLA loci mismatches is common, and carries a high engraftment failure rate, with a range of 10% to 20%. Further, cord blood cells are reported to be good source for the production of iPSC. Here, we report an analysis of allogeneic immunogenicity which focuses on engraftment of unrelated transplantation from HLA-homo cord blood.
Using Transplant Registry of Japanese Data Center for Hematopoietic Cell Transplantation, we could analyze 5017 Japanese CBT pairs who were typed as HLA-A, -B, -C, -DRB1 alleles at the field 1 and 2 level, and transplanted single unit of cord blood for the first time. Patient age was ranged from 0 to 80 years old (median 50), Patient with AML was 1,113, ALL 884, MDS 514, other hematological malignancy 1,007 and non-hematological malignancy 374. 20 patients were transplanted in 1999-2004, 1,484 in 2005-2010 and 3,513 in 2011-2016. Donor HLA homo and patient HLA hetero combination (homo-hetero) was found in 39 pairs, hetero-homo in 40, homo-homo in 21, hetero-hetero with HLA allele match in HVG vector in 236, hetero-hetero with one allele mismatch in 569 and hetero-hetero with more than 2 allele mismatch in 4112 pairs.
Of note, all of 39 HLA homo-hetero pairs obtained neutrophil engraftment (500/μl) at 10-51 day (median 20) after transplantation except one early death pair. Platelet engraftment (20,000/μl) was also obtained in all evaluable 30 pairs. Acute GVHD with grade Ⅱ-Ⅳ and grade Ⅲ-Ⅳ occurred in 17 pairs and 3 pairs of 38 evaluable pairs respectively. Multivariate competing risk regression analysis including clinical factors revealed that homo-hetero pairs (n=39) showed a comparative neutrophil engraftment risk (HR=1.18 p=0.285) compared with HLA allele match hetero-hetero pairs (n=236), favorable risk compared with hetero-hetero pairs with HLA 1 allele mismatch (n=569) and favorable risk compared with hetero-hetero pairs with HLA more than 2 allele mismatch (n=4112). Also, these homo-hetero pairs showed comparative mortality (HR 0.95 P=0.85), platelet engraftment ((HR 1.10 p=0.597) and a tendency of higher risk of acute GVHD (grade 2-4) HR 1.63. p=0.065) compared with HLA allele match hetero-hetero pairs.
Further, we obtained detailed information on HLA alleles and haplotypes of HLA-homo. 37 of 39 homo-hetero donors had conserved extended HLA haplotypes (HP-1 n=18, HP=2 n=8, HP=3 n=7, HP-4 n=5, HP-5 n=1) which were ethnicity specific and highly conserved through the entire HLA region, and one of two patient heterogeneous HPs invariably shared the same HP as donor HLA-homo HP, and another non-shared patient HP was mismatched with 1 to 4 HLA alleles of HLA-A, -B, -C and -DRB1 loci in the GVH direction in 33 of these 37 pairs. The KIR2DL1 epitope was donor C1/C1 and patient C1/C1 in all homo-hetero pairs, making the KIR2DL ligand match combination.
In conclusion, CBTs from homo-hetero showed a favorable engraftment rate (100%), which confirmed our previous preliminary report for 6 homo-hetero CBTs. HLA alleles of HLA-homo donor were consisted of major conserved extended HLA haplotypes. Those results carry an important implication, namely the possibility that HLA-homo iPSC transplantation results in favorable engraftment, and banking of iPSC with major conserved extended HLA haplotypes is recommended, and patients possessing a single conserved common HLA haplotype have a higher chance of yielding HLA-homo iPSC and promising allo-iPS-T.

Disclosures
Ichinohe: Janssen Pharmaceutical K.K.: Honoraria; Taiho Pharmaceutical Co.: Research Funding; Bristol-Myers Squibb: Honoraria; MSD: Research Funding; Ono Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; JCR Pharmaceuticals: Honoraria; Nippon Shinyaku Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Celgene: Honoraria; Takeda Pharmaceutical Co.: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Chugai Pharmaceutical Co.: Research Funding; Novartis.: Honoraria; Mundipharma: Honoraria; Astellas Pharma: Research Funding.