Targeting dipeptidyl peptidase IV (CD26) suppresses autoimmune encephalomyelitis and up-regulates TGF-beta 1 secretion in vivo.
CD26 or dipeptidyl peptidase IV (DP IV) is expressed on various cell types, including T cells. Although T cells can receive activating signals via CD26, the physiological role of CD26/DP IV is largely unknown. We used the reversible DP IV inhibitor Lys[Z(NO(2))]-pyrrolidide (I40) to dissect the role of DP IV in experimental autoimmune encephalomyelitis (EAE) and to explore the therapeutic potential of DP IV inhibition for autoimmunity. I40 administration in vivo decreased and delayed clinical and neuropathological signs of adoptive transfer EAE. I40 blocked DP IV activity in vivo and increased the secretion of the immunosuppressive cytokine TGF-beta1 in spinal cord tissue and plasma during acute EAE. In vitro, while suppressing autoreactive T cell proliferation and TNF-alpha production, I40 consistently up-regulated TGF-beta1 secretion. A neutralizing anti-TGF-beta1 Ab blocked the inhibitory effect of I40 on T cell proliferation to myelin Ag. DP IV inhibition in vivo was not generally immunosuppressive, neither eliminating encephalitogenic T cells nor inhibiting T cell priming. These data suggest that DP IV inhibition represents a novel and specific therapeutic approach protecting from autoimmune disease by a mechanism that includes an active TGF-beta1-mediated antiinflammatory effect at the site of pathology.
Steinbrecher
A
A
Neurological Diseases, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. andreas.steinbrecher@klinik.uni-regensburg.de
Reinhold
D
D
Quigley
L
L
Gado
A
A
Tresser
N
N
Izikson
L
L
Born
I
I
Faust
J
J
Neubert
K
K
Martin
R
R
Ansorge
S
S
Brocke
S
S
D000818:Animals; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005260:Female; D005620:Freund's Adjuvant / Q000008:administration & dosage; D006131:Growth Inhibitors / Q000502:physiology; D007165:Immunosuppression Therapy; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008213:Lymphocyte Activation; D008239:Lysine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000276:immunology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D006131:Growth Inhibitors; D004676:Myelin Basic Protein; D011480:Protease Inhibitors; D011759:Pyrrolidines; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C110164:lysyl-(Z(nitro))pyrrolidide; D005620:Freund's Adjuvant; D018819:Dipeptidyl Peptidase 4; D008239:Lysine