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Immune responses against islet allografts during tapering of immunosuppression - a pilot study in 5 subjects
Journal Contribution - Journal Article
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 = 0ยท035). In vitro
addition of tacrolimus but not MPA strongly inhibited CTL alloreactivity
during tapering and led to a significant shift to anti-inflammatory graftspecific
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.
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 = 0ยท035). In vitro
addition of tacrolimus but not MPA strongly inhibited CTL alloreactivity
during tapering and led to a significant shift to anti-inflammatory graftspecific
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.
Journal: Clinical & Experimental Immunology
ISSN: 0009-9104
Volume: 169
Pages: 190-198
Publication year:2012
Keywords:islet cell transplantation, cytotoxic T-lymphocytes, immunosuppression, tacrolimus, mycophenolte mofetil
Accessibility:Open