Interaction of AIDS-associated microbes with radiation

  • Dadachova, Ekaterina (PI)

Project: Research project

Project Details

Description

SUMMARY
The occurrence of certain AIDS-associated opportunistic infectious diseases combined with the emergence
of multidrug-resistant strains of bacteria and fungi has produced an urgent need for new approaches to
antimicrobial therapy. Five years ago we first suggested the use of radioimmunotherapy (RIT) as a novel
modality for treatment of opportunistic infections whereby radiolabeled specific monoclonal antibodies
(mAbs) are used to deliver microbicidal radiation to pathogens. This application proposes to further
investigate the potential of RIT in treatment of CN infection by utilizing longer lived radionuclides with more
powerful nuclear emissions, and mAbs with various isotypes which might combate infections with high
inoculum and as well as to identify the contribution of immune system towards RIT efficacy in
immunocompetent and immunocompromised hosts which would allow to develop RIT clinical protocols
aimed at specific patient populations. We hypothesize that radiolabeling capsule binding mAbs with
longer-lived radionuclides with the variety of energies would permit delivery of higher fungicidal doses
of radiation to the sites of the infection in the host. We propose to utilize Lead-212/Bismuth-212 parent-
daughter pair as an -emitter and radiolanthanides - as -emitters. We also hypothesize that if the
binding constants of IgGs and IgAs mAbs to glucoroxylomannan are close to each other - mAbs with IgA
isotype will be more efficient in RIT of CN as they will be able to deliver their radioactive cargo closer to the
cell body containing radiation-sensitive DNA and cellular machinery. We already possess the family of mAbs
with the same variable region but various isotypes. Finally, based on our experimental observations that the
profound effects of CN infection on the immune system make infection RIT outcomes much more dependent
on immune status than in cancer RIT - we hypothesize that immune system plays a significant role in the
outcome of infection RIT and we are planning to prove this hypothesis by evaluating contribution of
neutrophils, cytokines, complement and cellular immunity to the RIT. The proposed research will facilitate
clinical introduction of RIT of opportunistic CN infection. Understanding of immune mechanisms involved in
the RIT outcomes will help to devise clinical protocols with expanded therapeutic window for treatment of
patients in different stages of the disease.
StatusFinished
Effective start/end date9/15/108/31/12

Funding

  • National Institute of Allergy and Infectious Diseases: $415,000.00

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