Despite all efforts to improve HLA typing and immunosuppression, it is still impossible to prevent severe graft versus host disease (GVHD) which can be fatal. GVHD is not always associated with graft versus malignancy and can prevent stem cell transplantation from reaching its goals. Overall T-cell alloreactivity is not the sole mechanism modulating the immune defense. Innate immune system has its own antigens, ligands, and mediators. The bridge between HLA and natural killer (NK) cell-mediated reactions is becoming better understood in the context of stem cell transplantation. Killer immunoglobulin-like receptors (KIRs) constitute a wide range of alleles/antigens segregated independently from the HLA alleles and classified into two major haplotypes which imprints the person's ability to suppress or to amplify T-cell alloreactivity. This paper will summarize the impact of both activating and inhibitory KIRs and their ligands on stem cell transplantation outcome. The ultimate goal is to develop algorithms based on KIR profiles to select donors with maximum antileukemic and minimum antihost effects. 1. Introduction Allogeneic hematopoietic stem cell transplantation is a curative approach. Removal of residual malignant cells and relapse prevention by an intensive conditioning regimen and reinstitution of a successful posttransplant anticancer immune response are the essential benefits of this treatment modality. The current donor-recipient matching criteria involve multiple factors but the only immunological barrier taken into consideration is the human leukocyte antigen system (HLA). However, an important factor affecting the success is the function of natural killer (NK) cells which are closely controlled by KIRs that interact with specific HLA class I ligands. KIR genes are encoded within 100–200？kb region of the leukocyte receptor complex (LRC) located on chromosome 19 (19q13.4) and segregated independently from the HLA genes. Most of HLA identical donor-recipient matched pairs are actually KIR mismatched. Innate system involves natural killer cells which through binding to their ligands can inhibit or activate the anticancer or antidonor reactivity arising from HLA recognition. The KIR genes belong to the most polymorphic structures between all surface receptors, second only to MHC, and are the key regulators of NK cells. Since these receptors are located on natural killer cells, they are called killer immunoglobulin-like receptors (KIRs). KIRs may exert inhibitory or activating functions through iKIR and aKIRs. There are nine iKIR and six aKIR
References
[1]
P. Parham, “MHC class I molecules and KIRS in human history, health and survival,” Nature Reviews Immunology, vol. 5, no. 3, pp. 201–214, 2005.
[2]
W. Leung, “Use of NK cell activity in cure by transplant,” British Journal of Haematology, vol. 155, no. 1, pp. 14–29, 2011.
[3]
L. Ruggeri, M. Capanni, E. Urbani et al., “Effectiveness of donor natural killer cell aloreactivity in mismatched hematopoietic transplants,” Science, vol. 295, no. 5562, pp. 2097–2100, 2002.
[4]
K. Gagne, M. Bussson, J. D. Bignon et al., “Donor KIR3DL1/3DS1 gene and recipient Bw4 KIR ligand as prognostic markers for outcome in unrelated hematopoietic stem cell transplantation,” Biology of Blood and Marrow Transplantation, vol. 15, no. 11, pp. 1366–1375, 2009.
[5]
K. L. McQueen, K. M. Dorighi, L. A. Guethlein, R. Wong, B. Sanjanwala, and P. Parham, “Donor-recipient combinations of group A and B KIR haplotypes and HLA class I ligand affect the outcome of HLA-matched, sibling donor hematopoietic cell transplantation,” Human Immunology, vol. 68, no. 5, pp. 309–323, 2007.
[6]
A. Bishara, D. de Santis, C. C. Witt et al., “The beneficial role of inhibitory KIR genes of HLA class I NK epitopes in haploidentically mismatched stem cell allografts may be masked by residual donor-alloreactive T cells causing GVHD,” Tissue Antigens, vol. 63, no. 3, pp. 204–211, 2004.
[7]
H. J. Symons, M. S. Leffell, N. D. Rossiter, M. Zahurak, R. J. Jones, and E. J. Fuchs, “Improved survival with inhibitory killer immunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors after nonmyeloablative, HLA-haploidentical bone marrow transplantation,” Biology of Blood and Marrow Transplantation, vol. 16, no. 4, pp. 533–542, 2010.
[8]
D. Weisdorf, S. Cooley, S. Devine et al., “T cell-depleted partial matched unrelated donor transplant for advanced myeloid malignancy: KIR ligand mismatch and outcome,” Biology of Blood and Marrow Transplantation, vol. 18, no. 6, pp. 937–943, 2012.
[9]
M. Cook, D. Briggs, C. Craddock et al., “Donor KIR genotype has a major influence on the rate of cytomegalovirus reactivation following T-cell replete stem cell transplantation,” Blood, vol. 107, no. 3, pp. 1230–1232, 2006.
[10]
K. C. Hsu, C. A. Keever-Taylor, A. Wilton et al., “Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes,” Blood, vol. 105, no. 12, pp. 4878–4884, 2005.
[11]
K. Dalva, F. Gungor, E. Soydan Akcaglayan, and M. Beksac, “Two independent effects of immunoglobulin-like receptor (KIR) allele matching between siblings: inhibitory KIR, (IKIR) mismatches are associated with graft versus host disease (GVHD) while activatory KIR matches, (AKIR) and CGVHD are associated with graft versus leukemia (GVL),” Blood, vol. 108, supplement 1, Article ID 2912a, 2006.
[12]
H. J. Kim, Y. Choi, W. S. Min et al., “The activating killer cell immunoglobulin-like receptors as important determinants of acute graft-versus host disease in hematopoietic stem cell transplantation for acute myelogenous leukemia,” Transplantation, vol. 84, no. 9, pp. 1082–1091, 2007.
[13]
S. Giebel, I. Nowak, J. Dziaczkowska et al., “Activating killer immunoglobulin-like receptor incompatibilities enhance graft-versus-host disease and affect survival after allogeneic hematopoietic stem cell transplantation,” European Journal of Haematology, vol. 83, no. 4, pp. 343–356, 2009.
[14]
K. Stringaris, S. Adams, M. Uribe et al., “Donor KIR genes 2DL5A, 2DS1 and 3DS1 are associated with a reduced rate of leukemia relapse after HLA-identical sibling stem cell transplantation for acute myeloid leukemia but not other hematologic malignancies,” Biology of Blood and Marrow Transplantation, vol. 16, no. 9, pp. 1257–1264, 2010.
[15]
S. M. Davies, L. Ruggieri, T. DeFor et al., “Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants,” Blood, vol. 100, no. 10, pp. 3825–3827, 2002.
[16]
S. Giebel, F. Locatelli, T. Lamparelli et al., “Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors,” Blood, vol. 102, no. 3, pp. 814–819, 2003.
[17]
M. Bornh？user, R. Schwerdtfeger, H. Martin, K. H. Frank, C. Theuser, and G. Ehninger, “Role of KIR ligand incompatibility in hematopoietic stem cell transplantation using unrelated donors,” Blood, vol. 103, no. 7, pp. 2860–2861, 2004.
[18]
M. Schaffer, K. J. Malmberg, O. Ringdén, H. G. Ljunggren, and M. Remberger, “Increased infection-related mortality in KIR-ligand-mismatched unrelated allogeneic hematopoietic stem-cell transplantation,” Transplantation, vol. 78, no. 7, pp. 1081–1085, 2004.
[19]
D. W. Beelen, H. D. Ottinger, S. Ferencik et al., “Genotypic inhibitory killer immunoglobulin-like receptor ligand incompatibility enhances the long-term antileukemic effect of unmodified allogeneic hematopoietic stem cell transplantation in patients with myeloid leukemias,” Blood, vol. 105, no. 6, pp. 2594–2600, 2005.
[20]
D. de Santis, A. Bishara, C. S. Witt et al., “Natural killer cell HLA-C epitopes and killer cell immunoglobulin-like receptors both influence outcome of mismatched unrelated donor bone marrow transplants,” Tissue Antigens, vol. 65, no. 6, pp. 519–528, 2005.
[21]
N. Kr？ger, B. Shaw, S. Iacobelli et al., “Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR-ligand mismatch after dose-reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma,” British Journal of Haematology, vol. 129, no. 5, pp. 631–643, 2005.
[22]
S. S. Farag, A. Bacigalupo, M. Eapen et al., “The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry,” Biology of Blood and Marrow Transplantation, vol. 12, no. 8, pp. 876–884, 2006.
[23]
J. S. Miller, S. Cooley, P. Parham et al., “Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic HCT,” Blood, vol. 109, no. 11, pp. 5058–5061, 2007.
[24]
T. Yabe, K. Matsuo, K. Hirayasu et al., “Donor killer immunoglobulin-like receptor (KIR) genotype-patient cognate KIR ligand combination and antithymocyte globulin preadministration are critical factors in outcome of HLA-C-KIR ligand-mismatched T cell-replete unrelated bone marrow transplantation,” Biology of Blood and Marrow Transplantation, vol. 14, no. 1, pp. 75–87, 2008.
[25]
S. Cooley, E. Trachtenberg, T. L. Bergemann et al., “Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia,” Blood, vol. 113, no. 3, pp. 726–732, 2009.
[26]
S. Cooley, D. J. Weisdorf, L. A. Guethlein et al., “Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia,” Blood, vol. 116, no. 14, pp. 2411–2419, 2010.
[27]
J. M. Venstrom, T. A. Gooley, S. Spellman et al., “Donor activating KIR3DS1 is associated with decreased acute GVHD in unrelated allogeneic hematopoietic stem cell transplantation,” Blood, vol. 115, no. 15, pp. 3162–3165, 2010.
[28]
C. G. Brunstein, J. E. Wagner, D. J. Weisdorf et al., “Negative effect of KIR alloreactivity in recipients of umbilical cord blood transplant depends on transplantation conditioning intensity,” Blood, vol. 113, no. 22, pp. 5628–5634, 2009.
[29]
R. Willemze, C. A. Rodrigues, M. Labopin et al., “KIR-ligand incompatibility in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia,” Leukemia, vol. 23, no. 3, pp. 492–500, 2009.
