Immune responses against islet allografts during tapering of immunosuppression – a pilot study in 5 subjects

• Published in: Clinical and experimental immunology Vol. 169; no. 2; pp. 190 - 198
• Main Authors: Huurman, V. A. L., van der Torren, C. R., Gillard, P., Hilbrands, R., van der Meer‐Prins, E. P. M. W., Duinkerken, G., Gorus, F. K., Claas, F. H. J., Keymeulen, B., Roelen, D. L., Pipeleers, D. G., Roep, B. O.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2012; Blackwell; Oxford University Press; Blackwell Science Inc
• Subjects: Adult; Analytical, structural and metabolic biochemistry; Autoimmunity; Avidity; Biological and medical sciences; biomarkers; CD8 antigen; Cytokines; Cytokines - biosynthesis; cytotoxic T‐lymphocytes; Cytotoxicity; Diabetes mellitus; Donors; Female; Follow-Up Studies; Fundamental and applied biological sciences. Psychology; Graft rejection; Graft Survival - drug effects; Graft Survival - immunology; Humans; Immune response; Immunity; Immunity, Cellular; Immunosuppression; Immunosuppressive Agents - administration & dosage; Inflammation; islet cell transplantation; Islet cells; Islets of Langerhans; Islets of Langerhans - immunology; Islets of Langerhans Transplantation - immunology; Lymphocytes T; Male; Metabolites; Middle Aged; Mycophenolate mofetil; Original; Pancreatic islet transplantation; Pilot Projects; Risk factors; Side effects; T-Lymphocytes, Cytotoxic - immunology; Tacrolimus; Transplantation; Transplantation, Homologous; Human; Calcineurin inhibitor; Immune response; Enzyme; IMP dehydrogenase; Enzyme inhibitor; Homograft; cytotoxic T-lymphocytes; islet cell transplantation; Lactone; Biochemistry; Transplantation; Macrolide; Immunosuppression; Treatment; Tacrolimus; Surgery; Graft; Protein synthesis inhibitor; Oxidoreductases; Immunosuppressive agent; Mycophenolate mofetil; Cell; Cytotoxic T lymphocyte
• ISSN: 0009-9104; 1365-2249; 1365-2249
• DOI: 10.1111/j.1365-2249.2012.04605.x

Summary Transplantation of isolated islet of Langerhans cells has great potential as a cure for type 1 diabetes but continuous immune suppressive therapy often causes considerable side effects. Tapering of immunosuppression in successfully transplanted patients would lower patients' health risk. To identify immune biomarkers that may prove informative in monitoring tapering, we studied the effect of tapering on islet auto‐ and alloimmune reactivity in a pilot study in five transplant recipients in vitro. Cytokine responses to the graft were measured using Luminex technology. Avidity of alloreactive cytotoxic T Lymphocytes (CTL) was determined by CD8 blockade. The influence of immunosuppression was mimicked by in vitro replenishment of tacrolimus and MPA, the active metabolite of mycophenolate mofetil. Tapering of tacrolimus was generally followed by decreased C‐peptide production. T‐cell autoreactivity increased in four out of five patients during tapering. Overall alloreactive CTL precursor frequencies did not change, but their avidity to donor mismatches increased significantly after tapering (P = 0·035). In vitro addition of tacrolimus but not MPA strongly inhibited CTL alloreactivity during tapering and led to a significant shift to anti‐inflammatory graft‐specific cytokine production. Tapering of immunosuppression is characterized by diverse immune profiles that appear to relate inversely to plasma C‐peptide levels. Highly avid allospecific CTLs that are known to associate with rejection increased during tapering, but could be countered by restoring immune suppression in vitro. Immune monitoring studies may help guiding tapering of immunosuppression after islet cell transplantation, even though we do not have formal prove yet that the observed changes reflect direct effects of immune suppression on immunity.