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Blood, 15 October 2008, Vol. 112, No. 8, pp. 3488-3499.
Prepublished online as a Blood First Edition Paper on July 21, 2008; DOI 10.1182/blood-2007-07-103325.
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Submitted July 25, 2007
Accepted July 13, 2008
Temporal, quantitative and functional characteristics of single-KIR positive alloreactive NK cell recovery account for impaired graft versus leukemia activity after haploidentical HSCT
Luca Vago, Barbara Forno, Maria Pia Sormani, Roberto Crocchiolo, Elisabetta Zino, Simona Di Terlizzi, Maria Teresa Lupo Stanghellini, Benedetta Mazzi, Serena Kimi Perna, Attilio Bondanza, Derek Middleton, Alessio Palini, Massimo Bernardi, Rosa Bacchetta, Jacopo Peccatori, Silvano Rossini, Maria Grazia Roncarolo, Claudio Bordignon, Chiara Bonini, Fabio Ciceri, and Katharina Fleischhauer*
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), IRCCS H San Raffaele, Milano, Italy
Dipartimento di Scienze della Salute (DISSAL), Universita degli Studi di Genova, Genova, Italy
Hematology and Bone Marrow Transplantation Unit, IRCCS H San Raffaele, Milano, Italy
HLA Typing, Immunohematology and Transfusion Medicine Service, IRCCS H San Raffaele, Milano, Italy
Cancer Immunotherapy and Gene Therapy Program (CIGTP), IRCCS H San Raffaele, Milano, Italy
N. Ireland Histocompatibility and Immunogenetics Laboratory, Belfast City Hospital, Belfast, Northern Ireland
University "Vita-Salute San Raffaele", Milano, Italy
MolMed, Milano, Italy
* Corresponding author; email: fleischhauer.katharina{at}hsr.it.
In the present study we have characterized reconstitution of the NK cell repertoire after haploidentical CD34+ selected Hematopoietic Stem Cell Transplantation (HSCT) for high-risk hematologic malignancies. Analysis focused on alloreactive single-KIR+ NK cells, which reportedly are potent antileukemic effectors.
One month after HSCT, CD56bright/CD56dim NK cell subsets showed inverted ratio and phenotypic features. CD25 and CD117 downregulation on CD56bright, and NKG2A and CD62L upregulation on CD56dim, suggest sequential CD56bright-to-CD56dim NK cell maturation in vivo. Consistently, the functional potential of these maturation intermediates against leukemic blasts was impaired.
Mature receptor repertoire reconstitution took at least three months. Importantly, at this time-point, supposedly alloreactive, single-KIR+ NK cells were not yet fully functional. Frequency of these cells was highly variable, independently from predicted NK alloreactivity, and below 1% of NK cells in 3 out of 6 alloreactive patients studied.
In line with these observations, no clinical benefit of predicted NK alloreactivity was observed in the total cohort of 56 patients. Our findings unravel the kinetics, and limits, of NK cell differentiation from purified haploidentical hematopoietic stem cells in vivo, and suggest that NK cell antileukemic potential could be best exploited by infusion of mature single-KIR+ NK cells selected from an alloreactive donor.
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