EFFECT OF TERMINAL COMPLEMENT INHIBITION BY ECULIZUMAB ON T-CELL AND NATURAL KILLER CELL DEPLETION IN LIVING DONOR KIDNEY TRANSPLANT RECIPIENTS INDUCED WITH POLYCLONAL RABBIT ANTITHYMOCYTE GLOBULIN.

NEW IMMUNOSUPPRESSIVE AGENTS

B.K.P. Goh, P.G. Dean, S. Raghavaiah, M.D. Stegall
Transplantation Surgery, Mayo Clinic, Rochester/MN/UNITED STATES OF AMERICA

Body: Introduction: The mechanism of T-cell depletion by rabbit antithymocyte globulin (rATG) has been shown in vitro to be due to apoptosis and complement-mediated cell lysis. Recently, Eculizumab; a potent terminal complement inhibitor has been shown to be potentially useful in reducing acute humoral rejection in patients undergoing positive crossmatch kidney transplantation (+XMKTx). Thus, Eculizumab might reduce the efficacy of rATG by inhibiting complement-mediated cell death of lymphocytes. The aim of this study was to determine the effect of Eculizumab on the efficacy of rATG and hence determine the role of complement in rATG-induced lymphocyte cell death in +XMKTx. Methods: 56 patients who underwent kidney transplant were classified into 4 groups according to their induction regimen including: Group A: rATG induction alone, (1.5 mg/kg on days 0, 1, 2. 4); Group B: +XMKTx induced with rATG plus Eculizumab, (1.3 mg/m2 on day 0, 1); Group C: +XMKTx induced with rATG alone and a Control group: induction with Basiliximab alone. Peripheral blood T-cell subsets were measured 3-4 days after transplant (after 3 doses of rATG) and compared. Results: Terminal complement was completely blocked in eculizumab patients as determined by red blood cell lysis assays. Compared to no-rATG induction, groups A, B and C lead to significant depletion of all T-cell subsets. However, patients in group B (Eculizumab) had a small, but significant increase in total T cells compared to groups A and C. Importantly, only 1 of the rATG + eculizumab treated patients developed cellular rejection.

	Group A (rATG) N =20	Group B (+XMKTx -rATG + Eculizumab) N = 8	Group C (+XMKTx - rATG) N = 20	Control (Basilixumab) N = 8	P-value (A vs B)	P-value (A vs C)	P-value (B vs C)
CD45, 1000 cell/uL	0.103 ± .017	0.215 ± .037	0.096 ± .017	0.914 ± .090	.005	.757	.002
CD3, cells/uL	8.95 ± 1.68	22.5 ± 4.63	8.05 ± 2.04	583.0 ± 77.9	.023	.736	.003
CD4, cells/uL	4.60 ± 0.925	9.63 ± 1.388	1.85 ± 0.48	310.5 ± 55.0	.007	.011	.001
CD8, cells/uL	6.55 ± 1.12	13.75 ± 4.05	5.50 ± 1.53	259 ± 45.5	.027	.583	.026
CD16+ CD56, cells/uL	4.70 ± 0.798	6.38 ± 1.70	8.10 ± 1.80	122 ± 31.2	.319	.096	.578

Conclusion: Peripheral T-cells and NK cells are depleted by rATG in the presence of terminal complement inhibition by Eculizumab. However, Eculizumab may have a subtle inhibitory effect on peripheral blood T-cell depletion by rATG in kidney transplant recipients although this impairment does not appear to be clinically significant. We further conclude that the primary mechanism of T-cell depletion with rATG is independent of terminal complement activity.

Disclosure: All authors have declared no conflicts of interest.