Belatacept has been approved as a calcineurin inhibitor (CNI) replacement, but its optimal use has not been determined. We have performed a pilot trial using alemtuzumab induction and belatacept/sirolimus maintenance therapy. As previously reported, this regimen is effective to prevent acute rejection, avoids steroids/CNIs, and is associated with donor-specific hyporesponsiveness. We have studied the repopulating immune repertoire specifically examining the prevalence of cells with potential regulatory function (T regulatory cells, ΓΔ T cells, and transitional B cells) as a percentage of the overall repertoire. All patients (n=20, median 45 years, range 20-69) were studied longitudinally over 24 months post-transplantation. Profound lymphocyte depletion was achieved following induction. CD4+ and CD+8 cells repopulated slowly returning to baseline between 18 and 24 months. During T cell repopulation, CD4+CD25+Foxp3+ cells were increased during the first 12 months and then returned to baseline at month-18. Conversely, CD8+ effector memory cells failed to return to baseline after depletion. A increase of CD3+VΔ1+ cells and a decrease of CD3+VΔ2+ cells were noted post-depletion, and the frequency of CD3+VΔ1+ cells was greater than baseline at month-24. Thus, VΔ1+/VΔ2+ ratios were increased in CD8+ and CD4-CD8- cells. Unlike T cells, B cells rapidly repopulated to baseline within 6 months and exceeded baseline, peaking at month-18 without development of alloantibody. The repopulating B cells were predominantly naÏve cells, and both switched (CD27+IgD-) and un-switched (CD27+IgD+) memory B cells were significantly lower than baseline at post-transplant month-24. Increased transitional (CD27-CD38+IgDhi) and regulatory B cells (CD38hiCD24hi with high MFI of IgM/CD20) were observed post-transplantation. We have characterized the peripheral dynamics of repopulating T and B cells in this novel regimen and find that cells with potential immunological regulatory signatures are consistently increase post transplant: including regulatory CD4+ cells, increased transitional and regulatory B cells, and increased VΔ1+ cells/ elevated VΔ1+/VΔ2+ ratios. These data suggest that alemtuzumab induction followed by CNIs-free belatacept/rapamycin maintenance regimen may promote potential immune regulatory signatures that are in favorable to the development of post-transplant hypo-alloresponses.

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