Douglas E Gladstone
Johns Hopkins University, USA
Keynote: Arch Cancer Res
Allogeneic hematopoietic stem cell recipients may have performed antibodies directed against foreign HLA antigens. The use of partially HLA-mismatched allogeneic hematopoietic stem cell donors allows for the possibility of the presence of circulating HLA donor-specific antibodies (DSAs) in the recipient. The presence of DSAs at the time of stem cell infusion increases the risk of primary graft failure. Recently developed technology using solid phase immunoassays (SPIs) with fluorochromeconjugated beads has greatly improved the ability to detect and classify DSAs. When used in combination with the classic lymphocytotoxic complement-dependent and flow cytometric cross match tests, SPIs help provide DSA strength assessment. Both CD34+ cells and T-cells are required for donor engraftment; however, the expression of HLA antibodies varies between these cells: all HLA loci are expressed on CD34+ cells (HLA-A highest, HLA- DQ lowest); HLA-A and B expression is higher on CD34+ cells than on T cells; HLA-C expression is lower on CD34+ than on T cells. Parous females frequently harbor DSAs. DSAs tend to be of higher intensity when directed against haploidentical first-degree relatives. DSA assessment requires frequent monitoring as their relative strength can change over time. Importantly, patients who harbor flow cytometric cross match detectable DSA who are treated with a combination of plasma exchange with intravenous immune immunoglobulin, tacrolimus and mycophenolate mofetil can often lower DSA levels to well below flow cross match detection. Although the criteria that constitutes a prohibitive DSA is unknown, desensitization can result in engraftment rates as experienced in fully HLA-matched allogeneic blood or marrow transplantation recipients.
1. Gladstone D E and Bettinotti M P (2017) HLA donorspecific antibodies in allogeneic hematopoietic stem cell transplantation: challenges and opportunities. Hematology American Society of Hematology Education Program 17:645-650.
2. Leffell M S, Jones R J and Gladstone D E (2015) Donor HLA-specific Abs: to BMT or not to BMT? Bone Marrow Transplant 50(6):751-8.
3. Gladstone D E et al. (2013) Partially mismatched transplantation and human leukocyte antigen donorspecific antibodies. Biology of Blood and Marrow Transplantation 19(4):647-52.
4. Ciurea S O et al. (2015) Complement-binding donorspecific anti-HLA antibodies and risk of primary graft failure in hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplantation 21(8):1392-1398.
Douglas E Gladstone is an Associate Professor in the Department of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. He is a Clinical Director of the Outpatient Bone Marrow Transplant Unit. In 2017, he led an educational program discussing how to lower donor specific antibodies to permissible levels for allogeneic bone marrow transplantation at the Annual American Society of Hematology conference