Increased MHC Matching by C4 Gene Compatibility in Unrelated Donor Hematopoietic Stem Cell Transplantation

Abstract

HLA matching is a prerequisite for successful allogeneic hematopoietic stem cell transplantation (HSCT) because it lowers the occurrence and severity of graft-versus-host disease (GVHD). However, matching a few alleles of the classic HLA genes only may not ensure matching of the entire MHC region. HLA haplotype matching has been reported to be beneficial in HSCT because of the variation relevant to GVHD risk in the non-HLA region. Because polymorphism in the MHC is highly population specific, we hypothesized that donors from the Finnish registry are more likely to be matched at a higher level for the Finnish patients than donors from other registries. In the present study we determined 25 single nucleotide polymorphisms (SNPs) of the complement component 4 (C4) gene in the g-block segment of MHC from 115 Finnish HSCT patients and their Finnish (n = 201) and non-Finnish (n = 280) donor candidates. Full matching of HLA alleles and C4 SNPs, independently or additively, occurred more likely in the FinnishÀFinnish group as compared with the FinnishÀnon-Finnish group (P < .003). This was most striking in cases with HLA haplotypes typical of the Finnish population. Patients with ancestral HLA haplotypes (AH) were more likely to find a full HLA and C4 matched donor, regardless of donor origin, as compared with patients without AH (P < .0001). Despite the clear differences at the population level, we could not find a statistical association between C4 matching and clinical outcome. The results suggest that screening C4 SNPs can be advantageous when an extended MHC matching or HLA haplotype matching in HSCT is required. This study also supports the need for small population-specific stem cell registries.

Immunological Diversity Is a Cornerstone of Organismal Defense and Allorecognition across Metazoa

“…Allorecognition is central to two biological phenomena: mating, which ensures that gametes are fertilized by conspecifics and, in some cases, prevents self-mating (63,64); and tissue fusion, which occurs when colonial invertebrates compete for space (65) or in the context of sexual parasitism among deep-sea anglerfishes (66). Evolutionary derivatives of allorecognition systems persist within the vertebrates as the well-characterized MHC loci, which plays important roles in both mate choice and defense (67,68), as well as tissue compatibility (69). Allorecognition has been well studied in only a handful of organisms; we describe self/ nonself-discrimination systems in a poriferan sponge, a hydroid cnidarian, a colonial tunicate, and vertebrate anglerfishes.…”

BSHI guideline: HLA matching and donor selection for haematopoietic progenitor cell transplantation

“…HLA class I and II genes are separated by the MHC class III region, also described as the gamma block, which contains genes encoding immune regulatory proteins including the complement components Bf, C2 and C4. Comparison of SNPs within the complement C4A and C4B genes did not identify any association between SNP mismatching and transplant outcome (Clancy et al., 2019; Getz et al., 2020). Similarly, no significant associations between gamma block mismatching and unrelated donor HPCT outcomes were observed in a large retrospective cohort from the CIBMTR (Askar et al., 2019), nor in multivariate analysis of a single‐centre cohort (Maskalan et al., 2020).…”

“…The EBMT consensus recommendations (Ciurea et al, 2020) concluded that NIMA-mismatched siblings may be preferred over (Clancy et al, 2019;Getz et al, 2020). Similarly, no significant associations between gamma block mismatching and unrelated donor HPCT outcomes were observed in a large retrospective cohort from the CIBMTR (Askar et al, 2019), nor in multivariate analysis of a single-centre cohort (Maskalan et al, 2020).…”

HLA gamma block matching in unrelated hematopoietic stem cell transplantation and the development of graft versus host disease

“…In a study conducted by Petersdorf et al in 2007, HLA haplotype matching was shown to be associated with an increased risk of severe acute GvHD 3 . The Gamma block region, which includes the C4 gene, could be used as a marker when predicting haplotype matching due to its positive LD with its surrounding loci 2 . The C4 gene is not usually typed for genetic matching between the patient and donor in HSCT, but due to its evident role in disease development and haplotype matching, some scientists had suggested including non-HLA genes of the GB as an alternative or addition to traditional HLA typing 9 .…”

“…Even though data on the subject of GB matching in HSCT are limited, some studies have shown statistically significant results in association to GvHD occurrence, which could play a role in donor selection in HSCT. Some recent studies provided data showing that haplotype matching between patients and their donors has reduced the risk of severe GvHD, but they did not identify a significant association between GB matching and HSCT outcomes 2,10 . On the other hand, a study by Park et al suggested that C4 mismatch was a high-risk factor for the development of GvHD in unrelated HSCT 11 .…”