CD134 as target for specific drug delivery to auto-aggressive CD4+ T cells in adjuvant arthritis.
T cells have an important role during the development of autoimmune diseases. In adjuvant arthritis, a model for rheumatoid arthritis, we found that the percentage of CD4+ T cells expressing the activation marker CD134 (OX40 antigen) was elevated before disease onset. Moreover, these CD134+ T cells showed a specific proliferative response to the disease-associated epitope of mycobacterial heat shock protein 60, indicating that this subset contains auto-aggressive T cells. We studied the usefulness of CD134 as a molecular target for immune intervention in arthritis by using liposomes coated with a CD134-directed monoclonal antibody as a drug targeting system. Injection of anti-CD134 liposomes subcutaneously in the hind paws of pre-arthritic rats resulted in targeting of the majority of CD4+CD134+ T cells in the popliteal lymph nodes. Furthermore, we showed that anti-CD134 liposomes bound to activated T cells were not internalized. However, drug delivery by these liposomes could be established by loading anti-CD134 liposomes with the dipalmitate-derivatized cytostatic agent 5'-fluorodeoxyuridine. These liposomes specifically inhibited the proliferation of activated CD134+ T cells in vitro, and treatment with anti-CD134 liposomes containing 5'-fluorodeoxyuridine resulted in the amelioration of adjuvant arthritis. Thus, CD134 can be used as a marker for auto-aggressive CD4+ T cells early in arthritis, and specific liposomal targeting of drugs to these cells via CD134 can be employed to downregulate disease development.
Boot
Elmieke P J
EP
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. E.Boot@nl.genmab.com
Koning
Gerben A
GA
Storm
Gert
G
Wagenaar-Hilbers
Josée P A
JP
van Eden
Willem
W
Everse
Linda A
LA
Wauben
Marca H M
MH
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology*; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology*; D015704:CD4 Antigens / Q000096:biosynthesis / Q000276:immunology*; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods*; D005467:Floxuridine / Q000008:administration & dosage; D008081:Liposomes; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D015704:CD4 Antigens; D008081:Liposomes; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505718:Tnfrsf4 protein, rat; D005467:Floxuridine