Since 1990 we have performed over 450 simultaneous pancreas-kidney (SPK) transplants in patients with type 1 diabetes (T1D) and end-stage renal disease. Approximately 5% of our patients develop T1D recurrence, 5-20 years after transplantation, typically preceded by the reappearance of autoantibodies to islet autoantigens several years before symptoms; pancreas transplant biopsy reveals insulitis with variable degree of beta cell loss. These patients also have autoreactive T cells in the circulation, assessed with antigen-specific class II/I tetramers/multimers. Here we describe a transplant recipient with recently diagnosed recurrent diabetes, in the absence of rejection; he harbored autoreactive T cells in the circulation and pancreas transplant lymph node tissue, which were predominantly memory cells. Moreover, about 80% of the islet infiltrating T cells expressed the memory marker CD45R0 and most expressed CD2. Despite frank diabetes and poor stimulated C-peptide response, the biopsy also showed many preserved islets. Applying the concept of tissue biomarker directed therapy we treated the patient with a 3-month course of anti-CD2 (Alefacept). Treatment decreased the frequency of CD8 autoreactive T cells, at least temporarily, and affected the phenotype of these cells: 1) like the overall CD8+ T cell population, autoreactive CD8+ T cells with terminal memory phenotype (CD45RA+, CCR7-, CD27-) and differentiated effector memory T cells seemed more sensitive to Alefacept; 2) CCR4 expression (associated with a Th2 cytokine profile) was increased on autoreactive CD8 memory T cells one month after initiation of the treatment; 3) autoreactive CD4 T cells were detected at the end of the treatment, a subset of which also expressed CCR4. The withdrawal of Alefacept from the marker precluded the opportunity for further treatment. While the patient continued insulin therapy, he experienced improved metabolic control with hemoglobin A1C returning to near normal levels.