title: Relevance of cytotoxic alloreactivity under different immunosuppressive regimens in clinical islet cell transplantation.
abstract: Islet or beta cell transplantation provides a promising cure for type 1 diabetes patients, but insulin-independency decreases frequently over time. Immunosuppressive regimens are implemented attempting to cope with both auto- and alloimmunity after transplantation. We analysed the influence of different immunotherapies on autoreactive and alloreactive T cell patterns and transplant outcome. Patients receiving three different immunosuppressive regimens were analysed. All patients received anti-thymocyte globulin induction therapy. Twenty-one patients received tacrolimus-mycophenolate mofetil maintenance immunosuppression, whereas the other patients received tacrolimus-sirolimus (SIR, n = 5) or SIR only (n = 5). Cellular autoreactivity and alloreactivity (CTL precursor frequency) were measured ex vivo. Clinical outcome in the first 6 months after transplantation was correlated with immunological parameters. C-peptide levels were significantly different between the three groups studied (P = 0.01). We confirm that C-peptide production was correlated negatively with pretransplant cellular autoreactivity and low graft size (P = 0.001, P = 0.007 respectively). Combining all three therapies, cellular autoimmunity after transplantation was not associated with delayed insulin-independence or C-peptide production. In combined tacrolimus-SIR and SIR-treated patients, CTL alloreactivity was associated with less insulin independence and C-peptide production (P = 0.03). The percentage of donors to whom high CTLp frequencies were measured was lower in insulin-independent recipients (P = 0.03). In this cohort of islet cell graft recipients, clinical outcome in the first 6 months after transplantation correlates with the applied immunosuppressive regimen. An association exists between insulin-independence and lower incidence of CTL alloreactivity towards donor human leucocyte antigen. This observational study demonstrates the usefulness of monitoring T cell reactivity against islet allografts to correlate immune function with graft survival.
authors.affiliation: Department of Immunohaematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands. d.l.roelen@lumc.nl
authors.forename: D L
authors.initials: DL
authors.lastname: Roelen
authors.forename: V A L
authors.initials: VA
authors.lastname: Huurman
authors.forename: R
authors.initials: R
authors.lastname: Hilbrands
authors.forename: P
authors.initials: P
authors.lastname: Gillard
authors.forename: G
authors.initials: G
authors.lastname: Duinkerken
authors.forename: P W M
authors.initials: PW
authors.lastname: van der Meer-Prins
authors.forename: M F J
authors.initials: MF
authors.lastname: Versteeg-van der Voort Maarschalk
authors.forename: C
authors.initials: C
authors.lastname: Mathieu
authors.forename: B
authors.initials: B
authors.lastname: Keymeulen
authors.forename: D G
authors.initials: DG
authors.lastname: Pipeleers
authors.forename: B O
authors.initials: BO
authors.lastname: Roep
authors.forename: F H J
authors.initials: FH
authors.lastname: Claas
mesh_terms: D000328:Adult; D015551:Autoimmunity; D002096:C-Peptide / Q000096:biosynthesis; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000601:surgery*; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007328:Insulin / Q000008:administration & dosage; D007515:Islets of Langerhans / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D011182:Postoperative Care / Q000379:methods; D020123:Sirolimus / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016559:Tacrolimus / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D002096:C-Peptide; D007166:Immunosuppressive Agents; D007328:Insulin; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus