Suppression of murine experimental autoimmune encephalomyelitis by interleukin-2 receptor targeted fusion toxin, DAB(389)IL-2.
Previously we have shown that DAB(389)IL-2, a recombinant fusion toxin targeting IL-2R bearing cells, suppressed disease in the rat experimental autoimmune encephalomyelitis (EAE) model of acute multiple sclerosis (MS). Our present study demonstrates that DAB(389)IL-2 can also effectively suppress acute (A)-EAE, relapsing (R)-EAE and chronic (C)-EAE in mouse demyelinating models. DAB(389)IL-2 significantly suppressed mitogenic proliferation of spleen cells while mutant fusion proteins DA(glu53)B(389)IL-2 and DAB(389)IL-2(8-10) did not. EAE was successfully suppressed when DAB(389)IL-2 was administered in various regimens between days 1 and 15 post immunization in all three models. CD4(+)IL-2R(+) cells were reduced in the spleen but not in the lymph nodes of DAB(389)IL-2-treated mice during A-EAE while the number of CD8(+) cells was unchanged. DAB(389)IL-2 also significantly reduced the number of CD4(+), CD8(+), CD25(+), TCRgammadelta(+) phenotype and CD11b(+) macrophages/microglia within spinal cord lesions. These data strongly suggest that DAB(389)IL-2 specifically targeted myelin protein-activated CD4(+) T cells and strengthens the argument for the use of DAB(389)IL-2 in treatment strategies for MS.
Phillips
S Michael
SM
University of Pennsylvania School of Medicine, Philadelphia, 19104-6160, USA.
Bhopale
Mahendra K
MK
Hilliard
Brendan
B
Zekavat
Seyed Ali
SA
Ali
Mohamad Anwar Ramadan
MA
Rostami
Abdolmohamad
A
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004167:Diphtheria Toxin / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology; D051381:Rats; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D013116:Spinal Cord / Q000166:cytology / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology
D004167:Diphtheria Toxin; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox