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Blood, 4 June 2009, Vol. 113, No. 23, pp. 5999-6010.
Prepublished online as a Blood First Edition Paper on April 15, 2009; DOI 10.1182/blood-2008-10-183335.
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Submitted October 9, 2008
Accepted March 29, 2009
Invariant NKT - NK cell interactions dictate transplant outcome following  -galactosylceramide administration
Rachel D Kuns, Edward S Morris, Kelli PA MacDonald, Kate A Markey, Helen M Morris, Neil C Raffelt, Tatjana Banovic, Alistair LJ Don, Vanessa Rowe, Angela C Burman, Andrew D Clouston, Camile Farah, Gurdyal S Besra, Petr A Illarionov, Mark J Smyth, Steven A Porcelli, and Geoffrey R. Hill*
The Queensland Institute of Medical Research, Brisbane, QLD, Australia
Envoi Pathology, QLD, Australia
Faculty of Oral Biology & Pathology, UQCCR, University of Queensland, Brisbane, QLD, Australia
School of Biosciences, University of Birmingham, Birmingham, United Kingdom
Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY, United States
* Corresponding author; email: geoff.hill{at}qimr.edu.au.
Invariant natural killer T cells (iNKT cells) have pivotal roles in graft-versus-host disease (GVHD) and graft-versus-leukaemia (GVL) effects. iNKT cells are activated through their TCR by glycolipid moieties (typically the  -GalCer derivative KRN7000) presented within CD1d. We now investigate the ability of modified -GalCer molecules to differentially modulate alloreactivity and GVL. KRN7000 and the N-acyl variant, C20:2, were administered in multiple well established murine models of allogeneic stem cell transplantation (SCT). The highly potent and specific activation of all type 1 NKT cells with C20:2 failed to exacerbate and in most settings inhibited GVHD late after transplant while effects on GVL were variable. In contrast, the administration of KRN7000 induced hyper-acute GVHD and early mortality in all models tested. Administration of KRN7000, but not C20:2, was found to result in down-stream IL-12 and dendritic cell (DC)-dependent natural killer (NK) and conventional T cell activation. Specific depletion of host DC, IL-12 or donor NK cells prevented this pathogenic response and the induction of hyper-acute GVHD. These data demonstrate the ability of profound iNKT activation to modulate both the innate and adaptive immune response via the DC-NK cell interaction and raise concern for the use of -GalCer therapeutically to modulate GVHD and GVL effects.
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