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Alloreactivity in Renal Transplant Recipients with and without Chronic Allograft Nephropathy

Emilio D. Poggio^*,, Michael Clemente^*, Jocelyn Riley^*, Meagan Roddy^*, Neil S. Greenspan^,¶, Cora Dejelo^¶, Nader Najafian^#, Mohamed H. Sayegh^#, Donald E. Hricik and Peter S. Heeger^*,,

Departments of *Immunology and Nephrology and Hypertension, The Cleveland Clinic Foundation, Cleveland, Ohio; Departments of Medicine and Pathology, Case Western Reserve University, Cleveland, Ohio; ^¶Department of Pathology, University Hospitals of Cleveland, Cleveland, Ohio; and Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Boston, Massachusetts

Correspondence to Dr. Peter S. Heeger, Transplantation Research Program, Department of Immunology, The Cleveland Clinic Foundation, NB30, 9500 Euclid Avenue, Cleveland, OH 44195. Phone: 216-445-9356; Fax: 216-444-8372; E-mail: heegerp{at}ccf.org

ABSTRACT. The pathogenesis of chronic allograft nephropathy (CAN) involves both immunologic (antigen-dependent) and nonimmunologic (antigen-independent) mechanisms. In order to provide further insight into the immunologic basis of this disease, a cross-sectional analysis of cellular and humoral immunity in human renal allograft recipients with or without deteriorating renal function and biopsy proven CAN was performed. Interferon- enzyme-linked immunosorbent spot assays were used to assess cellular immunity to donor, or fully mismatched third-party stimulator cells (direct pathway), and to synthetic peptides derived from donor HLA molecules (indirect pathway). Anti-HLA antibodies were evaluated by flow cytometry using HLA-coated beads. Both the mean frequencies of donor-reactive peripheral blood lymphocytes and the number of individuals who responded to donor antigens per group were statistically higher in CAN patients versus control subjects (P < 0.02). Calculated ratios of donor/third-party enzyme-linked immunosorbent spot responses showed mean values of 2.61 ± 3.0 in the CAN group, with ratios of 0.50 to 0.72 ± 0.42 in control subjects (P < 0.001), confirming that direct, donor-specific cellular immunity predominated in patients with CAN. Fifty percent of CAN patients studied exhibited donor peptide reactivity compared with only 28.6% in control subjects. Finally, 33% of patients in the CAN group developed new posttransplantation anti-HLA antibodies compared with only 4% in the control group (P < 0.05). Overall, the results suggest that persistent cell-mediated and humoral alloimmunity contribute to the development of CAN and further demonstrate that anti-donor immunity in patients with CAN is heterogeneous. Immune monitoring to predict long-term outcome should include multiple measures of cellular and humoral immunity.

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