HLA–C KIR LIGANDS AND DONOR RECIPIENT KIR GENOTYPES INFLUENCE OUTCOME OF HAPLOIDENTICAL STEM CELL TRANSPLANTATION

6.2
TITLE: HLA–C KIR LIGANDS AND DONOR RECIPIENT KIR GENOTYPES INFLUENCE OUTCOME OF HAPLOIDENTICAL STEM CELL TRANSPLANTATION

Dianne De Santis,^1,2 Campbell Witt,^1,2 Arnon Nagler,³ Chaim Brautbar,^4,5 Frank Christiansen,^1,2 Amal Bishara.⁴

¹Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, Perth, Western Australia, Australia; ²Pathology, University of Western Australia, Nedlands, Western Australia, Australia; ³Bone Marrow Transplantation, Hadassah Medical Organization, Jerusalem, Israel; ⁴Tissue Typing and Immunogenetics, Hadassah Medical Organization, Jerusalem, Israel; ⁵Lautenberg Center for General and Tumor Immunology, Hebrew University Medical School, Jerusalem, Israel

Hematopoietic stem cell transplantation (SCT) from haploidentical donor (Haplo–SCT) is the ultimate refuge treatment for leukemia patients lacking HLA identical donors. Such donor/recipient pairs will be mismatched at a single HLA–Cw, but may be either matched or mismatched for the two major HLA–C epitopes C2 (shared by Cw 1,3,7,8) and C1 (shared by Cw 2,4,5,6), which differentially bind killer inhibitory (KIR) and activating receptors (KAR) expressed on natural killer (NK) cells. NK cells activity is therefore, controlled by a balance of both types of receptors. NK cells are the first subset of the immune system to recover numerically and functionally post Haplo–SCT, suggesting that these cells may play an important role in determining the outcome. We analyzed the outcome of 62 recipients (24 had ALL, 15 AML, 13 CML and 10 with other disease) of Haplo–SCT in relation to compatibility for HLA–C epitopes and the inhibitory and activating receptor genotypes of the donors and recipients. Of the 56 evaluated recipients (who survived more than 28 days), 29 were matched and 27 mismatched for C epitopes (12 in the GVHD, 11 in the rejection and 4 in both directions). Engraftment rates were higher in the matched group 90% as compared to 58% and 55% in the groups mismatched in the GVHD (P = 0.034) and rejection directions (P = 0.025), respectively. Survival rate was (28%) in the matched group as compared to (7%) in the mismatched groups (P = 0.05). Forty–one recipients were engrafted, of them 11 were mismatched in the GVHD direction, 9/11 (82%) developed GVHD compared to 12/30 (40%) of the matched group (P = 0.02). The presence of more than 4 activatory receptors in the donor was associated with the development of GVHD (P = 0.007). These data indicate that in choosing a haploidentical donor, both HLA–C locus and KIR, KAR genotypes of recipients and donors are important factors to be considered.