Five-year results of islet-alone transplantation match pancreas-alone transplantation with alemtuzumab, Tac/MMF, with strong suppression of auto and alloreactivity

A.M.J. Shapiro¹, C. Toso², S. Imes¹, A. Koh¹, T. Kin¹, D. O'Gorman¹, A. Malcolm¹, P. Dinyari¹, R. Owen¹, N.M. Kneteman¹, D.L. Bigam¹, R.Y. Calne³, P.A. Senior¹, B.O. Roep^4
1 University of Alberta, Surgery/Medicine, Edmonton, Canada; ² University of Geneva, Geneva, Switzerland; ³ University of Cambridge, Cambridge, U.K.; ⁴ Leiden University Medical Centre, Leiden, Netherlands Antilles

Objective: The utility of clinical islet transplantation has been questioned, with evanescent insulin independence over time. We hypothesized that potent T depletional induction with alemtuzumab, and tac/MMF would offer more durable immune protection, and would be better tolerated than sirolimus.
Methods: n=24 (mean age 49±9), with longstanding T1DM (mean 30±11 years), recurrent hypos (Clarke 5.5±1.4; Hypo 2,044±494) and lability (LI 572±66) and preserved renal function, received islet-alone transplants by percutaneous intraportal delivery (mean 829,900±200,000 IE, 10,938±2,300 IE/kg). Alemtuzumab 30mg was given on D-1, with maintenance tac (10ng/ml initially) and MMF (up to 2g/d).

Results: Of n=24 (longest follow-up 5.1yrs), 5 await a second infusion or are weaning from insulin presently. 92% (22/24) remain C-peptide positive with good control (A1C 6.3±0.2, Clarke 0±0, Hypo 0±0, LI 19±5, p<0.0001 vs baseline) . Of n=19 completed, 74% (14/19) remain insulin independent. 2/24 lost graft function following immunosuppressant withdrawal, after aseptic meningitis, and after nocardial pneumonia with brain abscess; both remain alive and have fully resolved. K-M survival for insulin independence at 5 years are 62% (alemtuzumab) vs 15% (Edmonton Protocol, EP), p=0.01.

65% of subjects treated with alemtuzumab tac/MMF achieved normal metabolic reserve vs 12% EP (p=0.01). None in the alemtuzumab group became sensitized by PRA. In terms of protective mechanisms, we found extreme polarization of IL-10 based signature (MLR - islet donor HLA reactivity) that likely reflects immune regulation. CD8 T-cell precursor frequencies to islet autoantigens were markedly suppressed, with significant increased responses to A2 epitopes, low antiviral responses to CMV, EBV and measles, and reduced CD8 autoreactivity to most islet epitopes except insulin B-chain, suggesting suppression of autoimmune reactivity.

Conclusions: Potent T-depletion with alemtuzumab and tac/MMF induced a protective, IL-10 regulated immune response, with substantially improved 5-year insulin independence rates that now compare favorably with those of pancreas-alone transplantation.