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Aims:Patients with Type 1 Diabetes (T1D) may become recipients of simultaneous pancreas-kidney (SPK) transplants to restore insulin secretion and kidney function; 5-6% of SPK transplant recipients develop T1D recurrence (T1DR) on follow-up despite immunosuppression that prevents rejection. T1DR is preceded by seroconversion for multiple autoantibodies and these are risk factors for T1DR. We are investigating the role of memory T cells and CXCR3 expression in T1DR.

Methods:  We report data from 8 SPK transplant recipients with T1DR and 29 with normal glucose tolerance (NGT). We studied autoreactive T cells in the peripheral blood and from the pancreas transplant (PT) and peri-PT lymph nodes (LN) using a pool of MHC class II tetramers loaded with T1D-associated peptides from multiple autoantigens. T cells were also analyzed for lineage and phenotype by flow cytometry (CD45RA, CD45RO, CCR7, PD-1, CXCR3, CCR4, CCR6).  PT biopsies were also stained for CXCR3, CD3, CD45RO and insulin.

Results:T1DR patients had higher frequency of autoreactive CD4 T cells than NGT patients (p=0.0014). Regardless of diabetes status, patients with autoantibody conversions had higher frequency of autoreactive CD4 T cells than patients who lacked or had persisting autoantibodies from prior to transplant (stable) (p=0.027). These increased frequencies were observed in the memory compartment and not in the naïve compartment. Most converters in the NGT and T1DR groups (all T1DR recipients were converters) had higher proportions of CXCR3, autoreactive CD4 memory T cells than stable SPK transplant recipients (p=0.0001). Furthermore, CXCR3+ memory T cells were also identified in the PT islet infiltrate in T1DR.

Conclusions: Our results support an association of memory, CXCR3+, autoreactive CD4 T cells with T1DR and autoantibody conversion. If validated by more extensive studies, CXCR3 may be a potentially suitable therapeutic target to antagonize recurrent islet autoimmunity, and perhaps islet autoimmunity in the native pancreas.