Design, synthesis, and evaluation of release kinetics of novel LFA-1 and TLR-4 inhibitor prodrugs for localized immunomodulation.

Each year, thousands of organ transplant recipients experience graft rejection due to acute immune responses of the innate and adaptive immune systems. Traditionally, systemic immunosuppression has been used to mitigate these immune responses against the graft, however this can lead to systemic toxicity and leave the recipient vulnerable to opportunistic infections. Localized immunosuppression, inhibiting immune responses against the transplant graft in a localized region while maintaining wider immune system function is therefore a topic of interest. This dissertation details the development and evaluation of release kinetics of novel prodrugs of TLR-4 antagonist TAK-242, which inhibits the early stages of innate immune inflammation, the development and biological evaluation of novel LFA-1 inhibitor compounds, which inhibit early T-cell trafficking of the adaptive immune system, and the development and evaluation of release kinetics of novel prodrugs of one of these novel LFA-1 inhibitors with poor leaving group ability under physiological conditions. Evaluation of the kinetics of release of the novel TLR-4 and LFA-1 inhibitor prodrugs successfully demonstrated efficient drug delivery with a high degree of control through structural modifications, and the biological studies on the novel LFA-1 inhibitors demonstrated the efficacy of LFA-1 inhibition in attenuating acute immune responses.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Doctoral

Grantor

Baylor University.

Year dc:date.issued

2026

Author dc:creator

• Sells, Chloë A., 1995-

Advisor dc:contributor.advisor

• Kane, Robert R.

• Immunosuppression.
• LFA-1.
• TLR-4.
• Immune responses.
• Inhibitor prodrugs.

Statement dc:rights

• Baylor University works are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. Contact libraryquestions@baylor.edu for inquiries about permission.

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/2104/14506

OAI identifier oai:identifier

oai:baylor-ir.tdl.org:2104/14506