P0413
THE ICOS+ TREG/ICOS+ TRESP BALANCE HAS A DECISIVE ROLE REGARDING THE PRESERVATION OF THE REMISSION PHASE IN SLE PATIENTS Free

An imbalance between CD4⁺-regulatory T-cells (Tregs) and CD4⁺-responder T-cells (Tresps) correlates with active disease flares in Systemic Lupus Erythematosus (SLE) patients. Both cell subsets consist of highly proliferative inducible T-cell co‐stimulatory molecule expressing (ICOS⁺-) and less proliferating ICOS^--Treg/Tresp cells.

In this study we aimed to examine the role of age-dependent differentiation for maintaining the ICOS⁺-Treg/ICOS⁺-Tresp or ICOS^--Treg/ICOS^--Tresp balance in SLE remission patients compared to active disease patients and to evaluate the influence of proliferation inhibitor or glucocorticoid therapy concerning the maintenance of these equilibria.

In 83 healthy volunteers, the ratio of ICOS⁺-Tregs/ICOS⁺-Tresps increased significantly with age, while that of ICOS^--Tregs/ICOS^--Tresps did not change. In 86 SLE remission patients, medication controlled disease activity was associated with an age-independently increased ratio of both ICOS⁺-Tregs/ICOS⁺-Tresps and ICOS^--Tregs/ICOS^--Tresps. In 13 active disease patients this increased ICOS⁺-Treg/ICOS⁺-Tresp ratio could not be maintained, due to an age-dependent earlier terminal differentiation of ICOS⁺-Tregs than of ICOS⁺-Tresps. The increased ratio of ICOS^--Treg/ICOS^--Tresp was maintained in active disease patients, but it decreased with age. This was attributable to an age-independent aberrant differentiation of ICOS^--Tresps and a resulting loss of age-dependent differentiation of ICOS^--Tregs. Especially the administration of proliferation inhibitors (azathioprine or mycophenolic acid) ensured prolonged differentiation and maintenance of functional ICOS⁺-Tregs with age. There was a similar but weaker effect of this medication on ICOS⁺-Tresps, causing a significant decrease of these cells with age. The proliferation capacity was neither affected in ICOS⁺-Tregs/Tresps nor in ICOS^--Tregs/Tresps. As a result, the ratio of ICOS⁺-Tregs/ICOS⁺-Tresps increased significantly with age and kept the patients in remission. In contrast, glucocorticoids increased the differentiation of ICOS^--Tregs especially in younger individuals, but had an adverse effect on their proliferation capacity.

Our data reveal a crucial role of the ICOS⁺-Treg/ICOS⁺-Tresp balance for the maintenance of self-tolerance and avoidance of disease flares in SLE. The used immunosuppressive therapy, especially the administration of proliferation inhibitors, has a decisive effect on the preservation of regular differentiation of all Treg/Tresp subsets with age, and most importantly avoids the terminal differentiation and immune senescence of ICOS⁺-Tregs.