The effect of simultaneous CD154 and LFA-1 blockade on the survival of allogeneic islet grafts in nonobese diabetic mice.
BACKGROUND
The rate of success in clinical transplantation of islets of Langerhans has dramatically improved with perspectives of wide-scale applicability for patients with type 1 diabetes. One drawback is the need for lifelong immunosuppression, which is associated with significant side effects. Immunomodulatory strategies devoid of side effects and with tolerogenic potential, such as co-stimulatory blockade, would be a great improvement if successful. In this study, the authors have explored the effect of simultaneous blockade of CD40/CD154 and intercellular adhesion molecule (ICAM)/lymphocyte function-associated antigen (LFA)-1 interactions.


METHODS
Spontaneously diabetic nonobese diabetic (NOD) mice underwent transplantation with allogeneic (C57BL/6) islets and were treated with anti-CD154 monoclonal antibody (mAb) (500 microg, three doses), anti-LFA-1 mAb (100 microg, three doses), or a combination of both in the early peritransplant period. In another set of experiments, LFA-1 engagement was impaired by transplanting islets isolated from ICAM-1-knockout (KO) mice.


RESULTS
Untreated animals rejected their grafts within 10 days. LFA-1 blockade alone did not result in improved islet graft survival, whereas CD154 blockade alone increased graft survival to 18 days. Simultaneous blockade of both pathways led to significantly improved islet graft survival to 30 days (ICAM-1-KO islets plus anti-CD154), 35 days (anti-LFA-1 plus anti-CD154), and 44 days (ICAM-1-KO islets plus anti-LFA-1 plus anti-CD154).


CONCLUSIONS
These data suggest that a synergistic effect for prolonged graft survival can be obtained by simultaneously targeting CD154 and LFA-1 in the challenging model of islet allotransplantation in NOD mice. The observation of similar results with anti-LFA-1 mAb and with ICAM-1-KO grafts suggests a key role of direct antigen presentation for the activation of LFA-1-driven signaling.
Berney
Thierry
T
Cell Transplant Center, Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue, Miami, FL 33136, USA.
Pileggi
Antonello
A
Molano
R Damaris
RD
Poggioli
Raffaella
R
Zahr
Elsie
E
Ricordi
Camillo
C
Inverardi
Luca
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000601:surgery; D004195:Disease Models, Animal; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D066298:In Vitro Techniques; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000379:methods; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D014184:Transplantation, Homologous / Q000276:immunology
D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D023201:CD40 Ligand