IMMUNOSUPPRESSION - PRE-CLINICAL AGENTS

C. Schroeder¹, T. Zhang², K. Ramirez-medina³, C. Avon², M. Pasetti³, R.N. Pierson iii², A.M. Azimzadeh^2
1Thoracic & Esophageal Surgery, Case Medical Center, Cleveland/UNITED STATES OF AMERICA, ²Surgery, Univ. of Maryland & Baltimore VA, Baltimore/MD/UNITED STATES OF AMERICA, ³Center For Vaccine Development, Univ. of Maryland & Baltimore VA, Baltimore/MD/UNITED STATES OF AMERICA

Body: Introduction. Current methods of immunosuppression are broadly inhibitory and thus associated with an increased risk of opportunistic infections and neoplasia. We have shown previously that CD40/CD154 interactions are necessary for both primary and secondary antibody (Ab) responses to viral antigens. Here we studied the effect of CD154 blockade (aCD154) and Cycloporine A (CsA) therapy on secondary responses to influenza, when the first immunization was performed before therapy, as might be done in wait-listed patients. Methods. Sixteen cynomologus monkeys were primary immunized with influenza vaccine in absence of immunosupression. A secondary boost immunization was administered during therapy with either anti CD154 monotherapy (IDEC-131, trough levels >100mg/ml, n=6), CsA (trough levels >300ng/ml,n=5), or left untreated (controls, n=5). The antibody responses against three influenza antigens (H1N1, H3N2, B) was measured by endpoint ELISA and expressed as EU/ml using a pool of monkey positive samples as standard. Results were expressed as the highest fold increase detected in four weeks following immunization or boost for the average of 3 antigens. A fold increase >1.4 was considered as a positive response. Results. 14 out of all 16 animals responded to the primary immunization performed in absence of therapy, with only 2 animals (in aCD154 and CsA groups) showing no increase in antibody levels in the context of existing antibodies at the time of immunization. In untreated controls, 4 of 5 animals mounted a strong secondary response while one with very high antibody levels at the time of boost showed no further increase after secondary immunization. With aCD154 mAb therapy, 4 out of 6 animals showed mild to strong IgM and IgG anti-flu immunity, and 2 demonstrated only IgM or IgG responses (Table 1). In contrast, CsA modulated secondary responses more strongly with 2 out of 5 animals producing low titers IgM and no IgG, and 3 of 5 showing IgG but no IgM Conclusions. Despite intact primary responses, CsA blunted secondary Ab responses to flu antigens. In contrast, antibody responses were only slightly modulated in anti-CD154-treated animals. This finding suggests that anti-CD154 treatment spares important facets the recipient’s adaptive immunity against opportunistic infections, potentially conferring a clinically significant advantage over conventional immunosuppression with respect to common pathogens.
Table 1. Influenza-specific humoral responses (mean±SD of fold increase [% positive])

Disclosure: All authors have declared no conflicts of interest.