A Distinct Region in Erythropoietin that Induces Immuno/Inflammatory Modulation and Tissue Protection.
Beneficial effects of short-term whole-molecule erythropoietin (EPO) therapy have been demonstrated on several animal models of diverse central nervous system pathology. However, the increased hematocrit induced by EPO-driven marrow stimulation greatly limits its potential for side effect-free therapy. We created a library of EPO-derived fragments based on the hypothesis that 2 distinct functions, erythropoiesis and tissue protection, reside in different regions of the molecule. Several small EPO-derived peptides within the Aβ loop of whole EPO molecule were screened for tissue protection in EAE mice. The 19-mer JM-4 peptide that contains 2 cysteine molecules consistently demonstrated the most potent clinical beneficial effects without producing hematocrit alterations in animal models of EAE. The JM-4-induced tissue protection was associated with modulation of the immunoregulatory process that drives inflammation and provokes subsequent autoimmune damage. Like the whole EPO molecule, JM-4 effectively modulated immune/inflammatory reaction within both the peripheral lymphatic tissue and central nervous system. The major effects induced by JM-4 include blocked expansion of monocyte/dendritic antigen presenting cell and T helper 17 cell populations, decreased proinflammatory cytokine production, and sharply enhanced expansion of the regulatory T-cell population. JM-4 shows promise for treatment of a broad spectrum of neural and non-neural conditions associated with inflammation.
Neurology Service, VA Medical Center of East Orange, East Orange, NJ, USA.|Department of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ, USA.
RuiRong
R
Yuan
Neurology Service, VA Medical Center of East Orange, East Orange, NJ, USA.|Department of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ, USA.
Bo
B
Wang
Neurology Service, VA Medical Center of East Orange, East Orange, NJ, USA.
Wei
W
Lu
Neurology Service, VA Medical Center of East Orange, East Orange, NJ, USA.|Department of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ, USA.
Yasuhiro
Y
Maeda
Neurology Service, VA Medical Center of East Orange, East Orange, NJ, USA. dowlinpc@njms.rutgers.edu.|Department of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ, USA. dowlinpc@njms.rutgers.edu.
Peter
P
Dowling
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology*; D004921:Erythropoietin / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D008198:Lymph Nodes / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D016716:PC12 Cells; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004921:Erythropoietin
Erythropoietin; Experimental autoimmune encephalomyelitis; Immunomodulation; Multiple sclerosis; Peptide