Combination of alpha-1 antitrypsin and doxycycline suppresses collagen-induced arthritis.
BACKGROUND
Rheumatoid arthritis (RA) is a complex disease characterized by autoimmune inflammation and joint destruction. Despite recent advances in RA treatment, current therapies require further improvement to overcome adverse events and ineffectiveness in some cases. By targeting different pathways/molecules using drug combinations, a better treatment can be obtained, whereas adverse events are reduced. In order to develop a new treatment option, the present study employs a gene therapy-based combination therapy using doxycycline and human alpha-1 antitrypsin (hAAT).


METHODS
DBA/1 mice were immunized with type II collagen to induce arthritis. Four weeks before immunization, they received a doxycycline containing diet and a single injection of adeno-associated virus vector expressing hAAT under the control of a tetracycline-dependent promoter. Control groups received doxycycline alone or saline. Macroscopic arthritis development as well as histopathological changes in the joint were evaluated. In addition, the effects of hAAT and doxycycline on lipopolysaccharide (LPS)- or tumor necrosis factor-alpha-induced interleukin (IL)-6 production from mouse fibroblast cells were also determined.


RESULTS
Combination therapy significantly reduced arthritis development and progression compared to the control group in respect to macroscopic as well as histopathological changes. Doxycycline and hAAT in combination also inhibited IL-6 expression from LPS-stimulated NIH/3T3 mouse fibroblast cells, indicating a contributing mechanism of arthritis inhibition.


CONCLUSIONS
The results obtained in the present study indicate that a combination therapy using AAT and doxycycline holds promising potential as a new therapy for RA.
Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA.
Christian
C
Grimstein
Young-Kook
YK
Choi
Minoru
M
Satoh
Yuanqing
Y
Lu
Xueying
X
Wang
Martha
M
Campbell-Thompson
Sihong
S
Song
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000229:Dependovirus / Q000187:drug effects / Q000235:genetics; D004318:Doxycycline / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007596:Joints / Q000187:drug effects / Q000473:pathology; D051379:Mice; D041681:NIH 3T3 Cells; D013752:Tetracycline / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000276:immunology / Q000627:therapeutic use*
D000906:Antibodies; D018501:Antirheumatic Agents; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D013752:Tetracycline; D004318:Doxycycline