Depleting syndecan-4+ T lymphocytes using toxin-bearing dendritic cell-associated heparan sulfate proteoglycan-dependent integrin ligand: a new opportunity for treating activated T cell-driven disease.
Because syndecan-4 (SD-4) is expressed by some (but not all) T cells following activation and serves as the exclusive ligand of dendritic cell-associated heparan sulfate proteoglycan-dependent integrin ligand (DC-HIL), we envisioned the DC-HIL/SD-4 pathway to be a therapeutic target for conditions mediated by selectively activated T cells. We conjugated soluble DC-HIL receptor with the toxin saporin (SAP; DC-HIL-SAP) and showed it to bind activated (but not resting) T cells and become internalized by and deplete SD-4(+) T cells. In hapten-sensitized mice, DC-HIL-SAP injected i.v. prior to hapten challenge led to markedly suppressed contact hypersensitivity responses that lasted 3 wk and were restricted to the hapten to which the mice were originally sensitized. Such suppression was not observed when DC-HIL-SAP was applied during sensitization. Moreover, the same infusion of DC-HIL-SAP produced almost complete disappearance of SD-4(+) cells in haptenated skin and a 40% reduction of such cells within draining lymph nodes. Our results provide a strong rationale for exploring use of toxin-conjugated DC-HIL to treat activated T cell-driven disease in humans.
Akiyoshi
Hideo
H
Department of Dermatology, Dermatology Section, Medical Service, University of Texas Southwestern Medical Center, Dallas Veterans Affairs Medical Center, Dallas, TX 75390, USA.
Chung
Jin-Sung
JS
Tomihari
Mizuki
M
Cruz
Ponciano D
PD
Ariizumi
Kiyoshi
K
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology; D003877:Dermatitis, Contact / Q000276:immunology / Q000517:prevention & control*; D005136:Eye Proteins; D005260:Female; D005455:Fluorescent Antibody Technique; D007167:Immunotherapy / Q000379:methods*; D000922:Immunotoxins / Q000494:pharmacology*; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D011971:Receptors, Immunologic / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D054789:Ribosome Inactivating Proteins, Type 1 / Q000494:pharmacology*; D000076985:Saporins; D012867:Skin / Q000187:drug effects / Q000276:immunology; D053671:Syndecan-4 / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D016207:Cytokines; D005136:Eye Proteins; C445671:Gpnmb protein, mouse; D000922:Immunotoxins; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C508306:Sdc4 protein, mouse; D053671:Syndecan-4; D000076985:Saporins