2010 American Transplant Congress
San Diego, CA, May 1-5,
Hypothesis: Tregulator/Teffector cell balance toward donor antigens will predict long term outcome in drug minimization trials.
Methods: Recipients of a 1 HLA haplotype mismatched kidney from living related donor [n=9] or a HLA 0MM deceased donor kidney[n=1] were induced with a single dose of Alemtuzumab, tacrolimus, and sirolimus. Tacrolimus was withdrawn at 3 mos. Fresh PBMC were sampled and tested for donor-specific regulation [DSR] at 6 mo intervals. DSR was measured by % bystander suppression of recall antigen [EBV or TT]-induced footpad swelling in the trans-vivo DTH assay. Suppression was triggered via indirect pathway, using a crude cell sonicate of donor Ags [dAg]. Patients were also monitored for humoral anti-donor immunity using Luminex single antigen beads, quantitated by MFI values for identified immunodominant donor class I and class II specificities.
Results: Median follow-up time was 4 yrs. All patients except 2 [see Table 1] have been successfully maintained on sirolimus monotherapy. Patients were classified according to regulation status over multiple timepoints: 1) Regulators= bystander suppression values were consistently [6/7,7/7 timepoints] >50%; 2) Non-regulators= no regulation at any time, or only a single timepoint of >50% regulation ; and 3) Intermediate= 2-3 timepoints of DSR >50%.
|No. of Patients||n=2||n=4||n=4|
|Sirolimus dose (mg/24h)||1||4**||1|
|Sirolimus level (ng/mL)||4||10||6|
|MFI Class I ***||100||500||111|
|MFI Class II***||0||5344||0|
**No other immunosuppressants except for:
1 pt on Tacrolimus 6 mg daily, MPA 540 mg bid and pred
1 pt on MPA 540 mg bid and pred
specific antibody measured by single bead Luminex assay
Conclusions: Sirolimus monotherapy after Alemtuzumab induction and CNI withdrawal was associated with better clinical outcomes in regulators (intermediate or total) compared to non-regulators. Regulators had lower DSA levels to donor HLA antigens. The tolerance signature in PBMC was dynamic, and thus may require longitudinal f/u to establish its stability for use in IS minimization trials.