Islet xenograft destruction in the hu-PBL-severe combined immunodeficient (SCID) mouse necessitates anti-CD3 preactivation of human immune cells

Introduction of the hu-PBL-SCID mouse model has yielded a potentially usefu l tool for research in transplantation. The aim of this study was to define the conditions necessary for a reconstituted human immune system to destro y in a consistent manner rat islet xenografts in the alloxan-diabetic hu-PB L-SCID mouse. We examined different time points of hu-PBL reconstitution, d ifferent transplantation sites of the islets and several hu-PBL reconstitut ion protocols. Major differences in graft destruction were observed between the different hu-PBL reconstitution protocols, irrespective of timing of h u-PBL reconstitution or site of transplantation. Although preactivation of hu-PBL did not improve the level of hu-PBL chimerism, histological and immu nohistochemical analysis of the grafts revealed a severe human lymphocytic infiltration and beta cell destruction only in the grafts of mice receiving preactivated hu-PBL. This beta cell injury resulted in impaired glucose to lerance, with in some animals recurrence of hyperglycaemia, and decreased i nsulin and C-peptide levels after glucose stimulation. Therefore, we conclu de that activation of hu-PBL prior to transfer is essential in achieving xe nograft infiltration and destruction in hu-PBL-SCID mice. The need for immu ne manipulation suggests that interactions between hu-PBL and xenografts in this model may be hampered by incompatibilities in cross-species adhesion and/or activation signals.