Elsevier

Human Immunology

Volume 67, Issue 3, March 2006, Pages 238-246
Human Immunology

MICA, MICB, and MHC Beta Block Matching in Bone Marrow Transplantation: Relevance to Transplantation Outcome

https://doi.org/10.1016/j.humimm.2006.02.012Get rights and content

Abstract

Genetic testing of the MHC is required for selection of donors for bone marrow transplantation. The outcome of related bone marrow transplantation is usually superior to that of unrelated bone marrow transplantation. This may be the result of inaccurate or incomplete genetic testing employed for selection of donor for transplantation. Based on MHC haplotype matching, MHC block matching has been developed for selection of potential unrelated donor. Block matching has been shown previously to improve outcome when added to the conventional method of human leukocyte antigen (HLA) typing for selection of donors. In this study, we have retrospectively analyzed 44 donor recipient pairs from the Australian Bone Marrow Donor Registry Repository with respect to matching of HLA-B and HLA-Cw by sequence-based typing and MICA and MICB by polymerase chain reaction–sequence specific primer and MHC beta block matching and correlated these results with survival. Beta block matching was correlated with MIC matching (p < 0.005) and with HLA-B and HLA-Cw matching. Patients who were HLA-B and -Cw matched had significantly improved survival when they were additionally matched for MHC beta block (pc = 0.04) or MIC (pc = 0.05).

Introduction

Bone marrow transplantation (BMT) is potentially curative for a number of malignant and non-malignant conditions originating in or involving bone marrow. Only 30% of patients in need of a transplant will have a genotypically matched sibling to serve as the donor. An unrelated donor is considered when a suitable human leukocyte antigen (HLA) identical sibling cannot be found in the family. It is known that the outcome of BMT from unrelated donors is inferior to that from HLA identical siblings which suggests undetected mismatching of HLA genes and/or mismatching in non-HLA polymorphic genes in the major histocompatibility complex (MHC) [1, 2, 3]. HLA identical siblings are matched throughout the MHC, including non-HLA polymorphic genes. Transplantation between these related pairs suggests that matching MHC haplotypes in identical siblings provides a superior outcome. Unrelated donors who are HLA matched with their patients and matched for non-HLA polymorphic genes may share the entire MHC region and be equivalent to HLA identical siblings. For MHC haplotype matching, the MHC block matching technique was developed to match for genomic blocks rather than for individual HLA loci and to enable the identification of donors and recipients who are matched for HLA and non-HLA sequences in the MHC equivalent to HLA identical siblings. MHC block matching is based upon the premise that the MHC includes the following polymorphic blocks [4, 5, 6]: the alpha block corresponding to a gene cluster around HLA-A, the beta block corresponding to a gene cluster around HLA-B and HLA-Cw, the gamma block corresponding to a gene cluster around Bf and C4, and the delta block corresponding to a gene cluster around HLA-DR and DQ.

One of these blocks, the beta block, spans about 300 kb [4] and contains the immunologically relevant HLA-B, HLA-Cw, MICA, and MICB genes. Retrospective and prospective studies have shown that matching donors and recipients for non-HLA DNA sequences in the MHC (beta and delta block matching) can result in improved patient survival and less severe acute graft versus host disease (GVHD) [7, 8, 9, 10]. It is possible that improved survival with MHC block matching may be attributed to matching of non-HLA genes such as MICA and MICB whose influence on outcome is not clear [1, 10].

MICA and MICB are highly polymorphic with at least 59 alleles for MICA (considering polymorphisms at both extracellular and transmembrane domains) and 19 alleles for MICB. MICA and MICB are located 46.4 and 141.2 kb centromeric to HLA-B, respectively [11, 12, 13]. Recent studies have shown that the highly polymorphic MIC antigens are expressed in transplanted organs and may cause early graft rejection [14, 15]. Thus, the polymorphisms of MICA and MICB may be involved in allogeneic BMT and GVHD [16]. Although it is known that the MIC gene products are ligands of NKG2D [17], an activating receptor on several immune cells, the actual roles of MICA and MICB in bone marrow transplantation have not yet been demonstrated. However, it is evident that the MHC beta block marker is also a marker for the MICA and MICB genes [18].

In this study we confirm the superior survival in BMT using beta block matched donors, characterize the correlations among beta block, MICA, MICB, and HLA-B, -Cw matching determined by sequence-based typing, and elucidate the effects of non-HLA polymorphic genes (MICA and MICB) on survival outcome of HLA-B and HLA-Cw matched pairs.

Section snippets

Patients

The study investigated 44 patients who had bone marrow transplantations with an unrelated donor between 1991 and 2001. DNA samples of all pairs were obtained from the Australian Bone Marrow Donor Registry (ABMDR) Repository kindly provided by Drs. Knowles, Holdsworth, and McCluskey as part of an international collaborative work forming a bone marrow transplantation study component of the 14th International HLA and Immunogenetics Workshop (14 IHIWS). Diagnoses and other recipient and donor

Number of Matched Pairs

Forty-four donor–recipient pairs with complete data of HLA, MIC, and MHC beta block matching were analyzed and are shown in Table 3. The correlations between these markers are shown in Table 4; 20, 27, 21, and 20 pairs were found to be fully matched at 5 HLA loci, HLA-B and -Cw by SBT and MICA and MICB by PCR-SSP typing and beta block matching, respectively. A comprehensive analysis of the effect of HLA matching by SBT, which is a collaborative work of 14 IHIWS, will be presented elsewhere.

Discussion

Our study provides the first evaluation of bone marrow transplants in which an assessment of matching based on combined typing data of MICA and MICB, sequence-based typing for HLA-B and HLA-Cw, and MHC beta block matching was analyzed. Our results demonstrated significant associations between MHC beta block matching and MICA and MICB matching. This is not unexpected because two of the three sequences amplified in the beta block matching technique are located at the 5′ regions of the MICA and

Acknowledgments

We most appreciate the excellent cooperation of the Australian Bone Marrow Donor Registry Repository and members of the bone marrow transplantation study component of the 14th International HLA and Immunogenetics Workshop, particularly Michael Knowles, Ronda Holdsworth, and James McCluskey for making cell lines and providing DNA samples and clinical data. K.K. has a scholarship of the Consortium Research Network of Medical Technology supported by the Ministry of Education, Thailand. C.L. was a

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    Supported by Post Graduate Program, Faculty of Medical Technology, Mahidol University and The Centre for Research and Development of Medical Diagnostic Laboratories, Khon Kaen University, Thailand.

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