Article

Relevance of cytotoxic alloreactivity under different immunosuppressive regimens in clinical islet cell transplantation.

Department of Immunohaematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands.
Clinical & Experimental Immunology (impact factor: 3.36). 02/2009; 156(1):141-8. DOI:10.1111/j.1365-2249.2008.03812.x pp.141-8
Source: PubMed

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.

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Keywords

anti-thymocyte globulin induction therapy
 
applied immunosuppressive regimen
 
beta cell transplantation
 
Clinical outcome
 
CTL alloreactivity
 
CTL precursor frequency
 
different immunosuppressive regimens
 
donor human leucocyte antigen
 
first 6 months
 
immunological parameters
 
Immunosuppressive regimens
 
islet allografts
 
islet cell graft recipients
 
pretransplant cellular autoreactivity
 
SIR-treated patients
 
tacrolimus-mycophenolate mofetil maintenance immunosuppression
 
three therapies
 
transplant outcome
 
transplantation correlates
 
type 1 diabetes patients