Robust T-Cell Responses to Aspergellosis in Chronic Granulomatous Disease: Implications for Immunotherapy

Cruz, C. Y., Lam, S., Hanley, P. J., Bear, A. S., Langston, C., Cohen, A. J., Liu, H., Porter, P., Martinez, C. A., Krance, R. A., Heslop, H. E., Rooney, C. M., Hanson, I. C. and Bollard, C. M. (2013). Robust T-Cell Responses to Aspergellosis in Chronic Granulomatous Disease: Implications for Immunotherapy. In: 19th Annual ISCT Meeting, Auckland, New Zealand, (S38-S38). 4/22/2013. doi:10.1016/j.jcyt.2013.01.141

Author Cruz, C. Y.
Lam, S.
Hanley, P. J.
Bear, A. S.
Langston, C.
Cohen, A. J.
Liu, H.
Porter, P.
Martinez, C. A.
Krance, R. A.
Heslop, H. E.
Rooney, C. M.
Hanson, I. C.
Bollard, C. M.
Title of paper Robust T-Cell Responses to Aspergellosis in Chronic Granulomatous Disease: Implications for Immunotherapy
Conference name 19th Annual ISCT Meeting
Conference location Auckland, New Zealand
Conference dates 4/22/2013
Journal name Cytotherapy   Check publisher's open access policy
Place of Publication Oxford, United Kingdom
Publisher Elsevier
Publication Year 2013
Year available 2013
Sub-type Published abstract
DOI 10.1016/j.jcyt.2013.01.141
ISSN 1465-3249
Volume 15
Issue 4
Start page S38
End page S38
Total pages 1
Collection year 2014
Language eng
Formatted Abstract/Summary
Chronic granulomatous disease (CGD) patients are highly susceptible to invasive aspergillosis and may benefit from aspergillus-specific CD4+ T-cell immunotherapy, which shows promise in diseases with known T cell defects like patients post bone marrow transplant. However, the aspergillus-specific CD4+ T-cell response is largely uncharacterized in CGD. Hence, we studied the aspergillus-specific T-cell response in both murine models of CGD and CGD patients. We hypothesized that T cell function is intact in CGD, but the response may be affected by the neutrophil dysfunction.

Our results showed that in both mice and humans, the CD4+ T-cell response to aspergillus was unimpaired in CGD. In fact, aspergillus specific T-cell frequencies were elevated in CGD in both mice (p<0.001) and humans (p=0.02). Further, murine models depleted of CD4+ T-cells, were resistant to aspergillus infection similar to their wildtype counterparts. In contrast, mice depleted of neutrophils, or neutrophils and CD4+ T-cells, developed clinical and pathologic evidence of pulmonary aspergillosis and increased mortality compared to non-depleted animals (p<0.05 in both cases). Additionally, despite having high levels of endogenous IFNγ CGD patients remain susceptible to aspergillosis. T-cells however may play a compensatory role against aspergillus, since we also demonstrated that CGD mice depleted of CD4+ T-cells have increased susceptibility to infection with the fungus (p=0.04). Nevertheless, these results suggest that aspergillus specific T cells, while functional, do not seem to provide complete protection against aspergillus in the setting of neutrophil deficient states such as CGD.

In conclusion, CGD patients remain susceptible to aspergillus despite having a robust aspergillus-specific CD4+ T-cell response. Therefore, in the setting of neutrophil dysfunction, T-cells are unlikely to be beneficial as a primary immunotherapeutic strategy for this disorder. Hence future studies investigating strategies to simultaneously enhance both the innate and the adaptive immune response are warranted.
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Institutional Status Non-UQ

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