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 the fusion molecule 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, Nantes, France.
Aubry
Venceslas
V
Renaudin
Karine
K
Séveno
Céline
C
Usal
Claire
C
Tezuka
Katsunari
K
Anegon
Ignacio
I
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000187:drug effects* / Q000276:immunology; D023201:CD40 Ligand / Q000187:drug effects* / Q000276:immunology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006084:Graft Rejection / Q000276:immunology / Q000628:therapy*; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology; D060889:Inducible T-Cell Co-Stimulator Protein; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; C499839:CD40Ig protein, recombinant; D060889:Inducible T-Cell Co-Stimulator Protein; D011993:Recombinant Fusion Proteins; D023201:CD40 Ligand