Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes

Abstract

The seemingly inexorable decline in insulin independence after islet transplant alone (ITA) has raised concern about its clinical utility. We hypothesized that induction immunosuppression therapy determines durability of insulin independence. We analyzed the proportion of insulin-independent patients following final islet infusion in four groups of ITA recipients according to induction immunotherapy: University of Minnesota recipients given FcR nonbinding anti-CD3 antibody alone or T cell depleting antibodies (TCDAb) and TNF-α inhibition (TNF-α-i) (group 1; n = 29); recipients reported to the Collaborative Islet Transplant Registry (CITR) given TCDAb+TNF-α-i (group 2; n = 20); CITR recipients given TCDAb without TNF-α-i (group 3; n = 43); and CITR recipients given IL-2 receptor antibodies (IL-2RAb) alone (group 4; n = 177). Results were compared with outcomes in pancreas transplant alone (PTA) recipients reported to the Scientific Registry of Transplant Recipients (group 5; n = 677). The 5-year insulin independence rates in group 1 (50%) and group 2 (50%) were comparable to outcomes in PTA (group 5: 52%; p>>0.05) but significantly higher than in group 3 (0%; p = 0.001) and group 4 (20%; p = 0.02). Induction immunosuppression was significantly associated with 5-year insulin independence (p = 0.03), regardless of maintenance immunosuppression or other factors. These findings support potential for long-term insulin independence after ITA using potent induction therapy, with anti-CD3 Ab or TCDAb+TNF-α-i.

Figure 1

Observed insulin independence in pancreas transplant alone and in islet transplant alone recipients based on induction immunosuppression administered. Islet transplant groups are indicated as follows: group 1 (UMN recipients, solid black), group 2 (CITR recipients receiving TCDAb +TNF-α-i, solid grey), group 3 (CITR recipients receiving TCDAb without TNF-α-i, grey checkered), group 4 (CITR recipients receiving IL-2RAb, vertical lines), group 5 (pancreas transplant alone recipients, white). Insulin independence was superior in groups 1 and 2 compared to groups 3 and 4 at 3 and 5 years posttransplant; groups 1 and 2 did not differ statistically from pancreas transplant alone (group 5). * p<0.01; ** p≤0.05

Figure 2

Insulin independence by induction agent, in the presence of TNF-alpha inhibitor therapy (wide bars) or absence of TNF-alpha inhibitor (narrow bars). Insulin independence was significantly lower at every time point in the ATG group in the absence of TNF-alpha inhibitor as compared to ATG with TNF-alpha inhibitor.