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 useful tool for research in transplantation. The aim of this study was to define the conditions necessary for a reconstituted human immune system to destroy in a consistent manner rat islet xenografts in the alloxan-diabetic hu-PBL-SCID mouse. We examined different time points of hu-PBL reconstitution, different transplantation sites of the islets and several hu-PBL reconstitution protocols. Major differences in graft destruction were observed between the different hu-PBL reconstitution protocols, irrespective of timing of hu-PBL reconstitution or site of transplantation. Although preactivation of hu-PBL did not improve the level of hu-PBL chimerism, histological and immunohistochemical 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 tolerance, with in some animals recurrence of hyperglycaemia, and decreased insulin and C-peptide levels after glucose stimulation. Therefore, we conclude that activation of hu-PBL prior to transfer is essential in achieving xenograft infiltration and destruction in hu-PBL-SCID mice. The need for immune 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.
Gysemans
C
C
Laboratory for Experimental Medicine and Endocrinology (LEGENDO), Katholieke Universiteit Leuven, Leuven, Belgium.
Waer
M
M
Laureys
J
J
Depovere
J
J
Pipeleers
D
D
Bouillon
R
R
Mathieu
C
C
D000818:Animals; D017252:CD3 Complex; D002678:Chimera / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000601:surgery; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology / Q000473:pathology; D006801:Humans; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D017710:Lymphocyte Transfusion; D008297:Male; D051379:Mice; D016513:Mice, SCID; D051381:Rats; D011913:Rats, Inbred BB; D016511:Severe Combined Immunodeficiency / Q000276:immunology*; D014183:Transplantation, Heterologous
D017252:CD3 Complex