myelin-basic-protein and Anaphylaxis

Administration of autoantigens under conditions that induce type 2 immunity frequently leads to protection from T cell-mediated autoimmune diseases. Such treatments, however, are inherently linked to the induction of IgG1 Abs and to the risk of triggering anaphylactic reactions. We studied the therapeutic benefit vs risk of immune deviation in experimental allergic encephalomyelitis of SJL mice induced by MP4, a myelin basic protein-proteolipid protein (PLP) fusion protein. MP4 administration in IFA induced type 2 T cell immunity, IgG1 Abs, and experimental allergic encephalomyelitis protection, and all three were enhanced by repeat injections. Despite high Ab titers, anaphylactic side reactions were not observed when MP4 was repeatedly injected in IFA or as soluble Ag s.c. In contrast, lethal anaphylaxis was seen after s.c. injection of soluble PLP:139-151 peptide, but not when the peptide was reinjected in IFA. Therefore, the Ab response accompanying the immune therapy constituted an anaphylactic risk factor only when the autoantigen was not retained in an adjuvant and when it was small enough to be readily disseminated within the body. Taken together, our data show that treatment regimens can be designed to boost the protective type 2 T cell response while avoiding the risk of Ab-mediated allergic side effects.

Topics: Anaphylaxis; Animals; Autoantigens; Encephalomyelitis, Autoimmune, Experimental; Female; Immunization; Immunoglobulin G; Interleukin-2; Interleukin-4; Mice; Myelin Basic Protein; Myelin Proteolipid Protein; Nerve Tissue Proteins; Recombinant Fusion Proteins; T-Lymphocytes

The ability of different forms of myelin peptides to induce tolerance for the treatment of preestablished murine experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, was evaluated. i.v. administration of myelin peptide-pulsed, ethylene carbodiimide-fixed syngeneic splenocytes, but not soluble myelin peptide monomers or oligomers, proved exceedingly effective at treating preestablished EAE, resulting in amelioration of disease progression. In addition to the lack of therapeutic efficacy of soluble peptide and peptide oligomer, administering them i.v. after the onset of clinical symptoms in many but not all peptide-induced EAE models led to a rapid-onset anaphylactic reaction characterized by respiratory distress, erythema, decreased body temperature, unresponsiveness, and, often, death. By using anti-IgE antibody treatments and mice with targeted mutations of the FcgammaRIII alpha-chain or the common gamma-chain of FcepsilonRI and FcgammaRI/III, we demonstrate that IgE crosslinking of FcepsilonRI appears to be necessary and sufficient for myelin peptide-induced anaphylaxis. The implications of these findings to myelin peptide/protein tolerance strategies for the treatment of multiple sclerosis are discussed.

Topics: Anaphylaxis; Animals; Body Temperature; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Female; Histamine; Immunoglobulin E; Immunoglobulins; Mice; Mice, Knockout; Myelin Basic Protein; Peptide Fragments; Receptors, IgE