Persistent long-term challenges in lymphocyte subsets induced by polyclonal antibodies

Background. Clinicians are well aware of the shortterm effects of immunosuppression by mono-or polyclonal antibodies. Little is known about long-term changes induced by these therapies. Methods. Forty-three renal allograft recipients were selected according to their initial postoperative immunosuppression: (1) BI group=basic immunosuppression with steroids and cyclosporine, n=16; (2) ATG group=basic immunosuppression plus polyclonal antibody antithymocyte globulin (ATG), n=11; and (3) OKT3 group=basic immunosuppression plus monoclonal antibody OKT3, n=16 patients. At intervals of 6 months, the following parameters were measured prospectively: lymphocyte surface antigens (HLA-DR, CD3, CD4, CD8, CD16, CD19, CD56, and CD57); serum and urine neopterin; serum amyloid A; and indirect and direct tests for herpes viruses. Results. The mean period of observation was 58.4 months. The most significant differences between the groups occurred for CD4(+) and CD8(+) T cells, The ratios of CD4(+) to CD8(+) cells (n=278 measurements) were significantly and persistently lower in the ATG group (P<0.001, Brown-Mood test), Five years after transplantation, the ATG group had a CD4(+) to CD8(+) cell ratio of (x) over tilde=0.6 versus (x) over tilde=1.7 in the OKT3 group and (x) over tilde=2.0 in the BI group. This inversion was due to a persistent depletion of the CD4(+) cells and an increased regeneration of the CD8(+) cells, in particular of the CD8(+bright)CD57(+) subpopulation. Extent and duration of CD4(+) depletion correlated with the cumulative ATG dose (r=0.7, P<0.05, Spearman rank correlation test). Conclusion. Therapy with polyclonal antibody ATG induces dose-dependent long-term changes in T-cell lymphocyte subsets, which persist over a period of years.