Absence of CD4CD25 regulatory T cell expansion in renal transplanted patients treated in vivo with Belatacept mediated CD28-CD80/86 blockade.
OBJECTIVE
Belatacept is a new recombinant molecule (CTLA4-Ig) that interferes with the second activation signal of T lymphocytes. CTLA4-Ig induced T cell allograft tolerance in rodents but not in primates. We examined the changes in peripheral lymphocyte subsets, including regulatory T cells, in renal transplant patients treated with Belatacept.


METHODS
A cross-sectional immunological study was carried out 6 months after transplantation in 28 patients enrolled in the Belatacept phase II study. Eighteen patients received Belatacept, mycophenolate mofetil and steroids (Belatacept group), while the control group of 10 patients received cyclosporine, mycophenolate mofetil and steroids (CsA group). Lymphocyte subsets were examined by flow cytometry. Foxp3 mRNA expression was measured by quantitative PCR.


RESULTS
The number of T lymphocytes and the percentage of CD3+ T cells were similar in both groups. However, the percentage of CD3+ CD4+ T cells was lower in the Belatacept group than in the control CsA group (B=42.5%+/-13.7 vs CsA=52.9%+/-9, p<0.005), and the percentage of CD3+ CD8+ cells was higher in the Belatacept group than in the control (B=32.9%+/-6.7 vs CsA=19.5%+/-8.2, p<0.0002). The percentage of CD19+ cells was similar in both groups. Among CD56+cells, only the percentage of CD16+ cells was significantly higher in the Belatacept group than in the control (B=82%+/-12 vs CsA=59.7%+/-25, p=0.01). Among CD4 and CD8 T cells the percentage of activated lymphocytes expressing CTLA4, HLA-DR or CD40L was similar in both groups. The percentage of CD4+CD25+ T cells was higher in the CsA group. The percentage of regulatory CD4+CD25+ cells with bright CD25 staining was similar in both groups (B=3.6+/-2.3% vs CsA=4.7+/-1.9%, ns) as was the expression of FoxP3.


CONCLUSIONS
Our results indicated that Belatacept did not induce regulatory T cell expansion in vivo. We suggest that Belatacept treatment should be maintained after transplantation to allow graft acceptance.
Chavez
H
H
Unité d'Immunologie Biologique, Hôpital de Bicêtre, France.
Beaudreuil
S
S
Abbed
K
K
Taoufic
Y
Y
Kriaa
F
F
Charpentier
B
B
Durrbach
A
A
D000069594:Abatacept; D000328:Adult; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D015704:CD4 Antigens / Q000032:analysis; D002465:Cell Movement / Q000187:drug effects; D016572:Cyclosporine / Q000008:administration & dosage; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D016030:Kidney Transplantation; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D023001:Transplantation Tolerance / Q000187:drug effects* / Q000276:immunology
D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D000069594:Abatacept; D016572:Cyclosporine