Tumour necrosis factor receptor gene therapy affects cellular immune responses in collagen induced arthritis in mice.
BACKGROUND
Collagen induced arthritis (CIA) is an animal model of rheumatoid arthritis (RA) amenable to immunotherapy directed against tumour necrosis factor alpha (TNFalpha).


OBJECTIVE
To evaluate whether local TNF receptor (TNF-R) gene therapy in DBA/1 mice exerts an influence beyond anti-inflammatory effects. Two measures of CIA pathogenesis were investigated-namely, immunity to collagen II (CII) 245-270 peptide (the major immunodominant epitope within bovine CII) and the preferential activation of T cell Vbeta8.2 variable region receptors in arthritic DBA/1 mice.


METHODS
DBA/1 mice received single periarticular injections of media or retroviral vectors containing LacZ or human TNF-R into affected arthritic paws at disease onset. Disease severity was monitored, immune responses towards the immunodominant bovine CII 245-270 and subdominant CII 334-360 peptide epitopes were assessed by ELISA, and T cell Vbeta usage was analysed by real time polymerase chain reaction for the LacZ transduced, TNF-R, and viral-free media treated control animals. The therapeutic influence of TNF-R gene transduction was compared with other groups at different times after treatment.


RESULTS
Reduced disease severity was seen 15-35 days after treatment, with a concomitant increase in immunity towards the subdominant CII 334-360 peptide epitope rather than the immunodominant CII 245-270 peptide in TNF-R treated animals. Early in the disease, TNF-R treated animals demonstrated a reduction of bias towards the otherwise predominant Vbeta8.2 T cell subset.


CONCLUSIONS
TNF-R gene therapy influences cellular immunity in CIA, leading to overall disease amelioration, thus suggesting that TNF inhibition may have therapeutic potential beyond the control of inflammation in RA.
Mukherjee
P
P
Department of Orthopedic Surgery, Wayne State University, 1 South, Hutzel Hospital, 4707 St Antoine Blvd., Detroit, MI 48201, USA.
Yang
S-Y
SY
Wu
B
B
Song
Z
Z
Myers
L K
LK
Robbins
P D
PD
Wooley
P H
PH
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000628:therapy*; D024043:Collagen Type II / Q000276:immunology; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007111:Immunity, Cellular; D016056:Immunodominant Epitopes / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008811:Mice, Inbred DBA; D010446:Peptide Fragments / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D012720:Severity of Illness Index; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics
D024043:Collagen Type II; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018124:Receptors, Tumor Necrosis Factor; C109168:T-cell receptor Vbeta 8.2; D007371:Interferon-gamma