Cellular islet autoimmunity associates with clinical outcome of islet cell transplantation.
BACKGROUND
Islet cell transplantation can cure type 1 diabetes (T1D), but only a minority of recipients remains insulin-independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function.


RESULTS
Twenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG) induction and tacrolimus plus mycophenolate mofetil (MMF) maintenance immunosuppression. Immunity against auto- and alloantigens was measured before and during one year after transplantation. Cellular auto- and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto- and alloantibodies. Clinical outcome parameters--including time until insulin independence, insulin independence at one year, and C-peptide levels over one year--remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively) and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively). Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome.


CONCLUSIONS
In this cohort study, cellular islet-specific autoimmunity associates with clinical outcome of islet cell transplantation under ATG-tacrolimus-MMF immunosuppression. Tailored immunotherapy targeting cellular islet autoreactivity may be required. Monitoring cellular immune reactivity can be useful to identify factors influencing graft survival and to assess efficacy of immunosuppression.


BACKGROUND
Clinicaltrials.gov NCT00623610.
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Volkert A L
VA
Huurman
Robert
R
Hilbrands
Gabriëlle G M
GG
Pinkse
Pieter
P
Gillard
Gaby
G
Duinkerken
Pieter
P
van de Linde
Petronella M W
PM
van der Meer-Prins
Minke F J
MF
Versteeg-van der Voort Maarschalk
Koen
K
Verbeeck
Behrooz Z
BZ
Alizadeh
Chantal
C
Mathieu
Frans K
FK
Gorus
Dave L
DL
Roelen
Frans H J
FH
Claas
Bart
B
Keymeulen
Daniel G
DG
Pipeleers
Bart O
BO
Roep
D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology*; D016381:Islets of Langerhans Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016896:Treatment Outcome
D001323:Autoantibodies