Week 4: A Deep Dive Into HLA Matching

Hello! I’m Sidharth, and this week I’ll be discussing HLA matching and analyzing transplant studies in an attempt to prevent “Off-the-Shelf” CAR T-cells from inducing dangerous immune responses.

Problem: In order to forge “Off-the-Shelf” CAR T-cells, HLA matching is required to avoid a potentially lethal immune response. Exactly how much HLA matching is needed?

Human leukocyte antigens (HLA) are responsible for helping our immune system distinguish itself from foreign bodies. In theory, matched, related HLA donors are the best candidates for transplantation, followed by matched unrelated donors. (Khaddour et al., 2022) When HLA-mismatching occurs, graft vs. host disease can result. In hematopoietic stem cell transplantations (HSCT), it appears to be crucial that donors are matched for the HLA-A, -B, -DR, -C, -DQ, and -DP genes. However, is this always the case? (Sheldon & Poulton, 2006)

Allele and Antigen Matching

Allele mismatches are significant at the DNA level but tend to have minor impacts on the immunological level. Unexpectedly, one group of scientists has concluded that allele mismatching does not increase the risk of graft failure while antigen mismatching is the opposite. Additionally, antigen mismatching for a single antigen can lead to graft failure. In a study of 51 recipients who were transplanted HCSs with a single mismatched antigen, 7 experienced graft failure. (Petersdorf et al., 2001)

Figure 1: Terminology for Donor Matching of HLA Alleles and Antigens 

Credit: (Petersdorf et al., 2001)

For efficient “Off-the-Shelf” CAR T-cells, there must exist 10-50 different cell lines that contain different homozygous HLA complexes that work for a majority of patients. One study demonstrates that a panel of ten donors homozygous for common HLA types selected from 10,000 individuals provided a complete HLA-A, HLA-B, and HLA-DR match for 37.7% of the recipients, and a beneficial match (one mismatch only) for 67.4%. (Taylor et al., 2005) However, is this enough? Will mismatches initiate immune rejection? How feasible is this method?

Another team of scientists has been genetically modifying heterozygous embryonic stem cells (ESCs) to create HLA-homozygous cells. They determined that a bank of 30 HLA-homozygous ESCs would match 38-59% of the U.S. population at HLA-A, HLA-B, and HLA-DR. (Riolobos et al., 2013) This method can likely be adapted for induced pluripotent stem cells.

Ultimately, matching every HLA gene will be incredibly difficult. However, using HLA-homozygous cells will help to lessen the cell lines needed. Furthermore, it’s important to consider HLA class I deficient cells. (Riolobos et al., 2013) Next week, I’ll continue to search for the path to “Off-the-Shelf” CAR T-cells. I hope you’ll continue to follow along!

Sidharth