KIR Ligand Incompatibility Model

The KIR ligand incompatibility model, also known as the “ligand-ligand” model was first suggested by the Perugia group, and predicts NK alloreactivity in the GVHD direction when the recipient lacks expression of an iKIR ligand (figure 4a) 31-34. This seminal study demonstrated the first clinical evidence of the efficacy of adoptive immunotherapy via NK alloreactivity 31,32. Utilizing HLA-mismatched haploidentical donors, Ruggeri and colleagues evaluated ninety two patients with high risk leukemia (57 with AML and 35 with ALL) using T- cell depleted graft to further investigate the role of NK cell alloreactivity based on the principles described by the “missing-self” hypothesis 31,32,37. To predict NK cell alloreactivity after alloHSCT, high resolution HLA typing of the donor and recipient pair was utilized to describe KIR-KIR Ligand (KIRL) mismatch. …show more content…
Patients received a conditioning regimen which included total body irradiation (TBI), thiotepa, fludarabine and anti-thymocyte globulin (ATG) and no additional GVHD prophylaxis 31,32. Patients were stratified based on KIR phenotypes expressing recognition of HLA-C alleles; the first with KIR ligand incompatibility in the GvH direction (donor-versus-recipient NK cell alloreactivity), and the second without32. In the presence of alloreactive NK cells in prior studies, this group demonstrated disease control by eradication of leukemia cells in vivo that resulted in marked improvement of survival in AML patients, with 65% event-free survival at five years in KIR ligand mismatched cohort compared to 5% in non-alloreactive group. These results were particularly notable given advanced stage disease ( 3rd complete remission or relapse) with 85% of patients with KIR-ligand