Abatacept treatment does not exacerbate chronic Mycobacterium tuberculosis infection in mice.
OBJECTIVE
Treatment of rheumatoid arthritis and other autoimmune disorders with anti-tumor necrosis factor (anti-TNF) agents is associated with an increased risk of reactivation of latent Mycobacterium tuberculosis. While the mechanism of action of abatacept is fundamentally different from that of anti-TNF therapies, its effect on the protective response to latent tuberculosis is not known. We undertook this study to determine the effect of abatacept treatment in a murine model of chronic M tuberculosis infection.


METHODS
Chronic M tuberculosis infection was established in C57BL/6 mice. Four months after infection, mice were treated for up to 16 weeks with abatacept, anti-murine TNF antibody, or vehicle. The primary end point was survival; body weight, bacterial load, histologic features, interferon-gamma (IFNgamma) production by T cells, and cellular infiltration were also assessed.


RESULTS
Abatacept- and vehicle-treated groups both maintained control of M tuberculosis infection, with 100% survival after 16 weeks of treatment. These 2 groups had no significant differences in body weight, no clinically relevant differences in bacterial load in the lungs, lymph nodes, or spleen, and no differences in the mean percentage of total or activated T cells, macrophages, neutrophils, or B cells, or in IFNgamma production in the lung or lymph nodes. In contrast, 100% mortality was seen in the anti-TNF antibody-treated group by week 9, with significant body weight loss and increased bacterial load in the lungs, lymph nodes, and spleen. Furthermore, the anti-TNF antibody-treated group had increased pathology consistent with the exacerbation of M tuberculosis infection.


CONCLUSIONS
Abatacept did not impair the ability of mice to control a chronic M tuberculosis infection. In contrast, mice treated with anti-TNF therapy showed increased pathology and bacterial load, with 100% mortality by week 9. The clinical significance of these findings has not yet been determined.
University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA.
Carolyn L
CL
Bigbee
Daryl G
DG
Gonchoroff
George
G
Vratsanos
Steven G
SG
Nadler
Helen G
HG
Haggerty
JoAnne L
JL
Flynn
D000069594:Abatacept; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000917:Antibody Formation / Q000187:drug effects; D018501:Antirheumatic Agents / Q000009:adverse effects*; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D018796:Immunoconjugates / Q000009:adverse effects*; D007371:Interferon-gamma / Q000378:metabolism; D008136:Longevity / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000276:immunology*; D013154:Spleen / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D015996:Survival Rate; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014376:Tuberculosis / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology
D000906:Antibodies; D018501:Antirheumatic Agents; D018796:Immunoconjugates; D014409:Tumor Necrosis Factor-alpha; D000069594:Abatacept; D007371:Interferon-gamma