The present invention features compositions for inhibiting both the IL-6 and the IL-21 pathways and methods of making and using such compositions. Our work to date indicates the importance of the redundancy of IL-6 and IL-21 to perform certain crucial functions. The pathways can be inhibited by inhibiting the ligands (i.e., IL-6 and IL-21) and/or their respective receptors (i.e., the IL-6 receptor and IL-21 receptor). Alternatively, or in addition, upstream and downstream effectors in the IL-6 and IL-21 pathways can be blocked. The agents used can be antibody or antibody-based proteins or peptides including circulating receptors, optionally coupled to an immunoglobulin or a portion thereof (e.g., the Fc region). Also provided are methods for using the compositions, for example, in organ transplantation, tissue grafting, or autoimmune disorders.
