TACI-Ig Does Not Affect C57Bl/6 Murine Response to Influenza Reinfection.
Authors: Ponce Rafael A. , Burleson Florence , Roque Richard , Hill Julie , Cabrit Mathilde , Broly Herve , Rogge Mark C. 
Published: October 2019

TACI-Ig, a soluble receptor Fc fusion protein with high affinity for BLyS and APRIL, is associated with decreased B-cells and reduced circulating immunoglobulin in mouse and nonhuman primates. TACI-Ig is in clinical evaluation for treatment of various B cell malignancies and autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. Because of its expected immunomodulatory activity on B cells, we have previously evaluated host response to TACI-Ig in a primary influenza infection model in C57Bl/6 mice. Influenza virus is a T-dependent antigen requiring intact and functional T-cells, B-cells and macrophage antigen processing for viral clearance. That study demonstrated the expected decrease in circulating mature B cells and serum immunoglobulin levels, but TACI-Ig did not suppress viral clearance or decrease survival. In the current study, we evaluated the effect of TACI-Ig administration on a recall response to a secondary infection using the murine influenza virus model. Mice were first exposed to influenza virus to initiate an active infection and primary immune response. Starting three weeks after infection, mice received ten SC injections of vehicle (Vehicle Control) or TACI-Ig (0.5 or 5.0 mg/kg) on a Mon-Wed-Fri schedule (Days 21–42). TACI-Ig administration resulted in decreased mature peripheral B cells, total IgG, total IgM, and influenza-specific IgG and IgM in both lung and serum. Recovery in these markers occurred over a six-week recovery period with the exception of some measurements of influenza-specific IgG and IgM in serum and lung, which remained decreased relative to Vehicle Control animals (Table 1). On Day 91, Vehicle Control and TACI-Ig-treated mice were rechallenged with influenza virus. In addition, a second control group (Primary Immunity Control) was subjected to a primary infection to provide age-matched animals for comparison. Irrespective of TACI-Ig treatment, viral clearance was significantly faster among influenza re-infected animals compared against Primary Immunity Controls, and no difference in viral clearance (Table 2) or survival was observed between TACI-Ig-treated animals and Vehicle Controls. These results demonstrate expected pharmacological effects on B-cells of TACI-Ig in C57Bl/6 mice, without apparent effects on influenza viral clearance or survival.

Table 1: Ratio of Influenza-specific IgG and IgM in Serum of TACI-Ig-treated Mice Relative to Concurrent Vehicle Controls (p-value) 0.5 mg/kg TACI-Ig 5.0 mg/kg TACI-Ig Influenza-Specific IgG (Sera) Day 49 0.68 (p = 0.08) 0.28 (p = 0.0006) Day 91 1.52 (p =0.15) 0.63 (p = 0.35) Influenza-specific IgM (Sera) Day 49 0.28 (p = 0.03) 0.02 (p = 0.001) Day 91 0.86 (p = 0.79) 0.78 (p = 0.58) Table 2: Influenza Plaque-Forming Units (per Lung) After Infection (Day 91) Primary Immunity Control Vehicle Control1 0.5 mg/kg TACI-Ig1 5.0 mg/kg TACI-Ig1 1 Secondary influenza infection Day 91 0 0 0 0 Day 92 7.88±0.03 0.98±0.28 0.23±0.23 0 Day 94 6.62±0.02 0 0 0 Day 98 4.35±0.03 0 0 0 Day 105 0 0 0 0