Stem cell based delivery of IFN-beta reduces relapses in experimental autoimmune encephalomyelitis.
Interferon-beta (IFN-beta), an approved treatment of multiple sclerosis (MS), produces only partial clinical responses. IFN-beta therapy has been limited by its short serum half-life and limited ability to cross the blood brain barrier. We have developed a means of delivering the IFN-beta gene both systemically and into the central nervous system (CNS) using bone marrow stem cells (BMSCs) as a vehicle and examined the therapeutic efficacy of this approach in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. A retroviral expression vector (pLXSN-IFNbeta) was used to stably transfect virus producer PA317 cells to generate retrovirus containing the IFN-beta gene which then was used to transduce BMSCs. IFN-beta engineered BMSCs were transplanted (i.v.) into mice that then were immunized with proteolipoprotein (PLP) to initiate EAE. IFN-beta-engineered BMSCs transplanted mice showed a significant inhibition of EAE onset, and the overall clinical severity was less compared to control groups. IFN-beta delivery strongly reduced infiltration of mononuclear cells possibly by inhibiting cell adhesion molecules. Reduced demyelination and increased remyelination were also observed in the IFN-beta treated group. Furthermore, inhibition of the pro-inflammatory cytokines TNF-alpha, IFN-gamma and IL-12 and enhanced expression of the anti-inflammatory cytokines IL-10, IL-4 and TGF-beta was observed in CNS tissue. In addition, mice receiving IFN-beta had reduced apoptosis and increases in growth promoting factors including BDNF, CNTF, PDGF and VEGF. These results suggest that BMSCs can be used as vehicles to deliver the IFN-beta into the CNS. This is a potentially novel therapeutic approach which might be used in MS and other diseases of the CNS in which drug access is limited.
Makar
Tapas K
TK
VA Maryland Healthcare System, Baltimore, MD 21201, United States. tmaka001@umaryland.edu
Trisler
David
D
Bever
Christopher T
CT
Goolsby
James E
JE
Sura
Karna T
KT
Balasubramanian
Shailesh
S
Sultana
Shireen
S
Patel
Niraj
N
Ford
David
D
Singh
Ishwar S
IS
Gupta
Aditi
A
Valenzuela
Reuben M
RM
Dhib-Jalbut
Suhayl
S
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology*; D016026:Bone Marrow Transplantation / Q000379:methods*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D018014:Gene Transfer Techniques; D020287:In Situ Nick-End Labeling; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D051379:Mice; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D055502:Secondary Prevention; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
D018952:Antigens, CD34; D016207:Cytokines; C090509:Icam1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D019010:Vascular Cell Adhesion Molecule-1; C435023:myelin proteolipid protein (139-151); D018799:Intercellular Adhesion Molecule-1; D016899:Interferon-beta; D053148:Caspase 3