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Previous work has shown that repetitive intranasal (i.n.) administration of the myelin basic protein peptide MBP Acl-9[4Y] induces tolerance in the TCR transgenic Tg4 EAE model. Chronic antigen stimulation of C04+ T cells was found to induce an anergic IL-l0-secreting regulatory phenotype in Th-I cells, protecting animals from EAE. Alternative routes for peptide administration were explored in the Tg4 model, to increase our understanding of the factors influencing peptide immunotherapy. Epicutaneously (e. c.) administered MBP Acl- 9[4Y] was slowly trafficked to the lymph nodes and spleen where C04+ T cells were activated. However, repetitive e.c. MBP Acl-9[4Y] administration did not reliably induce characteristics of C04+ T cell tolerance, attributed to the difficulty of controlling the e.c. administered MBP Acl-9 [4 Y] dose. Use of the subcutaneous (s.c.) route circumvented this problem, and titrated MBP Acl-9[4Y] doses were administered s.c. to Tg4 mice. Tolerance induced was proportional to the s.c. MBP Acl-9[4Y] dose administered, with higher doses better inducing an anergic, suppressive C04+ T cell phenotype, upregulation of IL-l0 secretion and protection from EAE. However, further increasing the s.c. peptide dose induced severe adverse effects in Tg4 (and Tg4 Rag-l -!-) mice, concomitant with high systemic inflammatory cytokine levels. Novel application of the technique of dose escalation to self-peptide immunotherapy allowed delivery of high peptide doses s.c. to Tg4 Rag-l +/+ and -/- mice without adverse effects. Escalating to higher s.c. peptide doses better induced tolerance, providing long-term protection of Tg4 Rag-l -/- mice from the spontaneous development of EAE. This demonstrates that low peptide doses administered s.c. during the escalation stage of treatment modulated the response of a monoclonal C04+ T cell population to subsequent high s.c. peptide doses. Collectively, these results show that route of antigen administration contributes to the outcome of peptide immunotherapy, which is also closely related to the peptide dose administered. Furthermore, we propose that dose escalation is essential for the safe and effective translation of peptide immunotherapy of auto immune disease into the clinic. |
