High HLA-DP Expression and Graft-versus-Host Disease

Julie Murphy, Mercer University College of Pharmacy

According to Harrison’s Principles of Internal Medicine, the human leukocyte antigen (HLA) complex, which is also known as the major histocompatibility complex (MHC), is a gene expressing region on chromosome six. These genes include HLA class I and II genes, which are critical for transplant histocompatibility and immunology. The HLA class I and II genes are responsible for producing MHC molecules which bind to small peptides to form ligands. These ligands are presented to T lymphocytes by antigen-specific T cell receptor (TCR) thus triggering an immune reaction. This system is closely related to allograft rejection and it is stated that allograft survival is highest when donor and recipient are HLA-identical.1

According to the New England Journal of Medicine, the major histocompatibility complex, class II, DP beta 1 (HLA-DPB1) gene is mismatched in 85% of transplants and it has been shown to cause life-threatening graft-versus-host disease (GVHD). A single-nucleotide polymorphism, rs9277534, is responsible for HLA-DP cell-surface expression with the rs9277534A allele causing low HLA-DP expression and the rs9277534G allele causing high HLA-DP expression.2

Title: High HLA-DP Expression and Graft-versus-Host Disease2
Design A Prospective Study; N= 3,508
Objective To determine the relationship between high HLA-DP expression and acute GVHD
Study Groups Haplotypes: rs9277534A-positive HLA-DPB1; n= 3,254

Haplotypes: rs9277534G-positive HLA-DPB1; n= 254

Methods Rs9277534 genotyping was conducted in recipients of transplants from unrelated donors for treatment of acute leukemia, chronic myeloid leukemia, or the myelodysplastic syndrome.
Duration 1988 to 2008
Primary Outcome Measure Occurrence of GVHD
Baseline Characteristics N/A
Results Hazard Ratios for Outcomes of HLA-DPB1 Mismatches in Transplant Recipients, According to the rs9277534 Allele Linked to the Mismatch*
Clinical End Point HLA-DPB1–Linked rs9277534
Allele
G Allele vs. A Allele in Recipient P Value for Interaction†
Donor Recipient Hazard Ratio (95% CI) P Value
Grade II, III, or IV acute GVHD A G

A

1.54 (1.25–1.89) <0.001 0.01
G G

A

1.01 (0.78–1.32) 0.90
Grade III or IV acute GVHD A G

A

1.50 (1.12–2.01) 0.007 0.28
G G

A

1.15 (0.80–1.66) 0.43
Chronic GVHD A G

A

1.09 (0.89–1.34) 0.39 0.66
G G

A

1.01 (0.78–1.32) 0.92
* The rs9277534 allele linked to the donor’s and recipient’s HLA-DPB1 mismatch was used to define four recipient–donor groups: A-A (n= 413 recipients and donors), A-G (n= 481), G-A (n= 331), and G-G (n= 212). All hazard ratios are for the comparison of recipients who had rs9277534G-linked HLA-DPB1 mismatches with recipients who had rs9277534A-linked mismatches.

† Tests for statistical interaction were performed to determine whether the effect of rs9277534G or rs9277534A in a transplant recipient was the same whether the donor had rs9277534G or rs9277534A. Thus, the P values provide information about whether the hazard ratio for a deleterious effect of HLA-DPB1 mismatching in a recipient with rs9277534G or rs9277534A when the donor had rs9277534G was the same as the hazard ratio when the donor had rs9277534A.

Adverse Events N/A
Study Author Conclusions HLA-DPB1 mismatching is not solely sufficient to cause GVHD but it can occur with the presence of the rs9277534G allele in the recipient and the rs9277534A allele in the donor.

According to the New England Journal of Medicine, it is suggested that the HLA-DPB1 rs9277534 haplotype is a risk factor for GVHD and supports the enhanced recognition of minor histocompatibility antigens during the donor recognition process. It is proposed that donors with low-expression mismatches can feasibly be used to reduce the number of high-risk mismatching transplants. The study shows that HLA-DPB1 expression can be used in donor selection to reduce the risk of acute GVHD. More studies are needed to assess the possibility of reduced risk with multiple low-expression HLA allele mismatches when compared to that of high-expression HLA allele mismatches. 2

References

  • Nepom GT. The Major Histocompatibility Complex. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. Harrison’s Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill; 2015. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1130&Sectionid=79749585. Accessed August 18, 2015.
  • Petersdorf EW, Malkki M, O’huigin C, et al. High HLA-DP Expression and Graft-versus-Host Disease. N Engl J Med. 2015;373(7):599-609.
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