Targeting the neonatal Fc receptor (FcRn) is not beneficial in an animal model of chronic neuritis

Abstract

The inhibition of the neonatal Fc receptor (FcRn) is a promising therapeutic pathway in certain autoimmune disorders to reduce the amount of circulating pathogenic IgG autoantibodies by interfering with their recycling system. FcRn antibodies are currently being tested in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). This study aimed to investigate the therapeutic potential of an antibody targeting FcRn in the intracellular adhesion molecule 1 (ICAM1)-deficient NOD mouse-a model representative for many aspects of human CIDP. After the onset of clinical signs of neuropathy, ICAM1-deficient NOD mice were assigned to treatment twice per week with anti-FcRn antibody, isotype control antibody (negative control) or intraperitoneal (administered) immunoglobulin (positive control). Disease severity was monitored using disease-specific assessments for ataxia and paresis such as grip strength measurements. Serum immunoglobulin levels and peripheral nerve immune cell infiltration were quantified. Treatment with anti-FcRn antibody did not ameliorate disease progression, as determined by clinical scores and grip strength analysis. Disease progression was reduced in the positive control animals receiving immunoglobulin. Consistent with the clinical results, the composition of infiltrating immune cells was not altered in the peripheral nerve of anti-FcRn antibody-treated mice compared to controls. However, in anti-FcRn antibody-treated mice, significantly lower IgG levels were detectable compared to controls. These findings suggest that targeting the FcRn recycling system does not influence disease progression in the NOD-ICAM1-deficient mouse model of CIDP. Further studies will elucidate whether the reduction of IgG levels was insufficient to deplete pathogenic autoantibodies or whether the major inflammatory driver in the NOD-ICAM1-deficient mouse animal model is mediated by factors other than pathological immunoglobulins.

Keywords: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP); ICAM-deficient NOD mouse; Immune-mediated neuropathy; Intravenous immunoglobulins (IVIg); Neonatal Fc receptor (FcRn).

Fig. 1

Treatment with anti-FcRn antibody does not ameliorate disease progression. Clinical evaluation of diseased ICAM1-deficient NOD mice treated with anti-FcRn antibody (blue), isotype control antibody (black) or hipIg (grey) for 7 weeks. A Paresis score: limb clasping test: score of 0: limps splayed outwards to keep balance; 1: limps are continuously retracted (every limp separately counted); summed 5: severe motor impairments; 6: death due to neuropathy. B Ataxia score: walking test to assess skilled walking and measure both forelimbs and hindlimbs. Slight foot faults were scored with 1; severe ones scored 2 for every limb; summed score 9: moribund; 10: death due to neuropathy. Depicted is mean ± SEM. Delta score of C paresis and D ataxia between the start and endpoint of treatment was determined to illustrate disease progression. For calculation, scores from endpoint were divided by the scores at day 0. Depicted is mean ± SEM (asterisks indicate significance: *p < 0.05; **p < 0.01; unpaired Student’s t-test). E Grip strength (force in Newton) analysis of diseased ICAM1-deficient NOD mice treated for 50 days with anti-FcRn antibody (blue), isotype control antibody (black) or hipIg (grey). Three independent measurements per animal were averaged. Depicted is mean ± SEM (asterisks indicate significance: *p ≤ 0.05; Mann–Whitney test). F After 50 days of treatment, serum levels of mouse IgM and IgG were determined using ELISA. Depicted is mean ± SEM (asterisks indicate significance: **p < 0.01; unpaired Student’s t-test)

Fig. 2

Treatment with anti-FcRn antibody did not affect nerve cell infiltration. Immunohistochemical staining of sciatic nerves of affected ICAM1-deficient NOD mice treated for 50 days with anti-FcRn antibody, unspecific control antibody or hipIg. T cells (CD3, green), B cells (B220, red) and cell nuclei (DAPI, blue) staining revealed no major differences in nerve cell infiltration or composition between the three treatment groups. Representative images are shown