Effect of Subcutaneously Administered Co-stimulation Blockade on T cell Sub-Populations in New Onset Type 1 Diabetes

A recent proof of concept phase II trial demonstrated prevention of C-peptide decline in newly-diagnosed patients with type 1 diabetes (T1D) through administration of the drug Abatacept by intravenous infusion. Abatacept blocks the CD80/CD86 co-stimulation pathway, upon which lymphocytes are dependent for their function. Arrest of C-peptide loss was associated with a decrease in peripheral blood central memory CD4⁺ (CD45RO⁺CD62L⁺) cells, and a corresponding increase in naïve (CD45RO⁻CD62L⁺) CD4⁺ cells. Regulatory (CD4⁺CD25^high) T cells (Tregs) were also reduced by treatment, but this did not relate to clinical outcome. We aimed to build on these findings by investigating the effect of Abatacept on sub populations of CD4⁺ T cells in newly-diagnosed T1D patients. 

Abatacept was self-administered via subcutaneous injection for 6 months at the normal therapeutic dose to T1D patients diagnosed within 100 days. Using fresh blood flow cytometry we confirmed that Abatacept significantly increased the proportion of naïve T cell populations – as defined by expression of CD45RA and CCR7 – across conventional CD4⁺ T cells (Tconv-N), (p=0.0015), regulatory CD4⁺ T cells (Treg-N) (p=0.0010) and CD8⁺ T cells (CD8-N) (p=0.016); decreased the proportion of effector memory T cells (Tem: CD45RA^-CCR7^-) in the same subsets (p=0.016, 0.0003 and 0.0064 respectively) and decreased the percentage of Tregs (CD25hi CD127lo) (p=0.00015). Of note, one of the largest and most significant Abatacept-induced changes was a reduction in the proportion of cells with an activated T follicular helper cell (Tfh) phenotype (CXCR5⁺PD-1⁺ICOS^-) within the memory Tconv and memory Treg populations (p=0.0005 and p = 0.0210 respectively).

Our findings indicate that subcutaneously administered Abatacept has similar effects on CD4⁺ subsets as previously reported, and extend these findings to include subsets involved in lymph node follicular immune responses.