Background The CD40-CD40L pathway is a potential target for the treatment of autoimmune diseases, as CD40 is a costimulatory receptor on antigen presenting cells (APCs) critical for the induction and maintenance of an immune response through binding CD40L on T cells. In the absence of CD40, both humoral and cellular responses to foreign antigens are severely impaired. In particular, disruption of this pathway prevents the development of disease in lupus-prone mice.
Objectives The objective of this work is to evaluate whether prophylactic and therapeutic treatment with an antagonistic anti-CD40 antibody prevents and reverses nephritis and other manifestations of lupus in lupus-prone mice.
Methods NZB/W-F1 mice were i.p. administered anti-CD40 prophylactically or therapeutically at various doses once or twice per week. Prophylactic treatment of NZB/W-F1 mice began at 26 weeks of age and continued for 9 weeks, while therapeutic treatment was initiated in NZB/W-F1 mice after they developed severe proteinuria (urine protein ≥300 mg/dL). Proteinuria was monitored weekly by urinalysis, and at study termination blood and spleen cells were analyzed by flow cytometry. Additionally, histological analysis of kidney, spleen, and salivary glands were performed, as well as gene transcription analysis of the kidney by microarray.
Results As expected, prophylactic and therapeutic administration reduced the number of splenic germinal center (GC) B cells and T follicular helper cells (Tfh). Prophylactic treatment blocked development of proteinuria and extended survival in NZB/W-F1 mice. Significantly, therapeutic anti-CD40 treatment reversed established, severe proteinuria in NZB/W-F1 mice and extended their survival. In agreement, the kidneys and salivary glands of treated mice exhibited reduced inflammation compared to control mice, and the kidneys exhibited lower CD40, IFN-I and chemokine gene signatures compared to controls. Interestingly, anti-CD40 decreased expression of genes in kidney belonging to the “hepatic fibrosis” pathway, possibly explaining the improvement of kidney function.
Conclusions Anti-CD40 treatment prevents the onset and reverses ongoing nephritis and sialadenitis in NZB/W-F1 mice. Resolution of ongoing nephritis results in restoration of low or normal urine protein levels. Thus, treatment with an antagonistic anti-CD40 is a strong candidate for clinical study in SLE.
Disclosure of Interest S. Perper Employee of: Abbvie, S. Westmoreland Employee of: Abbvie, Z. Liu Employee of: Abbvie, M. Duval Employee of: Abbvie, J. Seagal Employee of: Abbvie, B. McRae Employee of: Abbvie, S. Clarke Employee of: Abbvie