Anti-CD3 therapy of type 1 diabetes results in a temporary halt of its pathogenesis but does not constitute a permanent cure. One problem is the reinfiltration of islets of Langerhans with regenerated, autoaggressive lymphocytes. We aimed at blocking such a reentry by neutralizing the key chemokine CXCL10. Combination therapy of diabetic RIP-LCMV and NOD mice with anti-CD3 and anti-CXCL10 antibodies caused a substantial remission of diabetes and was superior to monotherapy with anti-CD3 or anti-CXCL10 alone. The combination therapy prevented islet-specific T cells from reentering the islets of Langerhans and thereby blocked the autodestructive process. In addition, the local immune balance in the pancreas was shifted toward a regulatory phenotype. A sequential temporal inactivation of T cells and blockade of T-cell migration might constitute a novel therapy for patients with type 1 diabetes.Type 1 diabetes (T1D) is a serious autoimmune-mediated disease characterized by the progressive destruction of insulin-producing b-cells in the islets of Langerhans in the pancreas. Several attempts have been made to block the autoimmune destruction of these b-cells. One of the most promising therapies targets T cells using anti-CD3 antibodies such as hOKT3g1, teplizumab, and otelixizumab (also known as ChAglyCD3), which have been evaluated in several clinical trials of patients with new and recently diagnosed T1D, including the DEFEND-1 study (otelixizumab) and the Protégé study (teplizumab) (1-4). Similar to preclinical animal models (5,6), treatment with anti-CD3 antibodies was effective in decelerating the pathogenesis of T1D in clinical trials (1,7,8). Administration of anti-CD3 antibodies results in the inactivation of conventional T cells and the expansion of previously constrained regulatory T-cell (Treg) populations (9,10). Unfortunately, in the majority of treated patients, prevention of the decline in b-cell function lasted no longer than 1-2 years (1,2,8,11,12). In addition, many patients did not respond to the treatment, for unknown reasons (13).Several combination therapies (CTs) to achieve long-term protection in the majority of patients with T1D have been assessed in preclinical models. In addition to anti-CD3 antibodies, several immunomodulatory agents have been used, including administration of nasal proinsulin (14), Lactococcus lactis-secreting interleukin (IL)-10/proinsulin (15), cyclosporine A and vitamin D3 analog (TX527) (16), IL-1 receptor antagonist (17), anti-CD20 antibody (18), fingolimod (FTY720) (19), the selective sphingosine 1 phosphate 1 modulator ponesimod (20), dipeptidyl peptidase-4 inhibitor MK626 (21), and HSP60 peptide p277 (22). Many of these CTs were superior to monotherapies. However, with the exception of CTs with anti-CD3 antibody/fingolimod tested in the LEW.1AR1-iddm rat model (19) and anti-CD3 antibody/ponesimod investigated in the NOD mouse model (20), none included blocking cell migration into the islets. To avoid side effects associated with traditional immunosuppressive drugs,...