Rapid destruction of encapsulated islet xenografts by NOD mice is CD4-dependent and facilitated by B-cells: innate immunity and autoimmunity do not play significant roles.
BACKGROUND
Spontaneously diabetic NOD mice rapidly reject microencapsulated islet xenografts via an intense pericapsular inflammatory response.


METHODS
Tilapia (fish) islets were encapsulated in 1.5% alginate gel microspheres. Recipients in series 1 were spontaneously diabetic NOD mice and streptozotocin-diabetic nude, euthymic Balb/c, prediabetic NOD, and NOR (a recombinant congenic strain not prone to autoimmune diabetes) mice. Recipients in Series 2 were STZ-diabetic NOD, NOD-scid, NOD CD4 T-cell KO, NOD CD8 T-cell KO, and NOD B-cell KO mice.


RESULTS
In Series 1, encapsulated fish islet grafts uniformly survived long-term in nude mice but were rejected in Balb/c and, at a markedly accelerated rate, in spontaneously diabetic NOD, streptozotocin-diabetic NOD and NOR recipients. Histologically, intense inflammation (macrophages and eosinophils) surrounding the microcapsules was seen only in NOD and NOR recipients. In Series 2, encapsulated fish islets uniformly survived long-term in NOD-scid and NOD CD4 KO mice; graft survival was markedly prolonged in B-cell KO (P<0.001) but not CD8 KO mice.


CONCLUSIONS
The rapid rejection of alginate encapsulated islet xenografts by NOD mice is not solely a consequence of beta-cell directed autoimmunity nor is it merely a vigorous innate immune response. Graft rejection requires CD4 T-cells, is facilitated by B-cells, and does not require CD8 T-cells.
Xu
Bao-You
BY
Department of Pathology, IWK Health Centre, Halifax, Nova Scotia, Canada.
Yang
Hua
H
Serreze
David V
DV
MacIntosh
Rebecca
R
Yu
Weiming
W
Wright
James R
JR
D000818:Animals; D015551:Autoimmunity; D015704:CD4 Antigens / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004804:Eosinophils / Q000378:metabolism; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D007249:Inflammation; D007515:Islets of Langerhans / Q000166:cytology; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D016131:Lymphocyte Subsets; D008214:Lymphocytes / Q000166:cytology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008819:Mice, Nude; D008863:Microspheres; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000379:methods*; D016896:Treatment Outcome
D015704:CD4 Antigens