Inhibition of chronic rejection and development of tolerogenic T cells after ICOS-ICOSL and CD40-CD40L co-stimulation blockade.
BACKGROUND
: Blockade of the CD40-CD40L pathway results in long-term allograft survival but does not prevent chronic rejection. ICOS-ICOSL are members of the CD28-B7 family that play an important role in T-cell activation.


METHODS
: The authors analyzed the effect of single or combined treatment with an anti-ICOS monoclonal antibody and CD40 immunoglobulin (Ig) on acute and chronic rejection of heart allografts in rats.


RESULTS
: Treatment with anti-ICOS resulted in a modest but significant prolongation of allograft survival. Treatment with CD40Ig resulted in long-term graft survival but the cardiac grafts developed chronic rejection lesions. Combined CD40Ig+anti-ICOS treatment led to indefinite graft survival in all recipients and a significant decrease of chronic rejection lesions compared with CD40Ig alone. Importantly, four of the seven CD40Ig+anti-ICOS-treated recipients showed a complete absence of chronic rejection lesions, whereas all of the CD40Ig-treated recipients showed chronic rejection. The CD40Ig+anti-ICOS group also showed significant decreased graft infiltration, decreased antidonor cytotoxic T-lymphocyte activity, and decreased alloantibodies compared with the CD40Ig-treated group. Adoptive transfer of splenocytes indefinitely prolonged allograft survival, whereas those depleted of T cells did not, suggesting the development of T-regulatory mechanisms.


CONCLUSIONS
: These data indicate that the chronic rejection mechanisms that are CD40-CD40L independent are ICOS-ICOSL dependent. These results were obtained with conservation of cognate immune responses and development of tolerogenic T cells.
Guillonneau
Carole
C
Institut National de la Santé et de la Recherche Médicale, Unit 643, and Institut de Transplantation et de Recherche en Transplantation, Nantes, France.
Aubry
Venceslas
V
Renaudin
Karine
K
Séveno
Céline
C
Usal
Claire
C
Tezuka
Katsunari
K
Anegon
Ignacio
I
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology*; D060889:Inducible T-Cell Co-Stimulator Protein; D008024:Ligands; D008285:Major Histocompatibility Complex; D008297:Male; D011506:Proteins / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous
D000945:Antigens, Differentiation, T-Lymphocyte; D019013:CD40 Antigens; D060889:Inducible T-Cell Co-Stimulator Protein; D008024:Ligands; D011506:Proteins; D023201:CD40 Ligand