Studies show that the interactions between autoreactive T cells and β cell-derived peptides bound to major histocompatibility complex (pMHC) molecules are required to trigger the development of type 1 diabetes (T1D). However, autoreactive T cells have extremely lower reactivity to their cognate antigens as compared to non-self-reactive T cells, but how they are still able to elicit autoimmune responses and mediate β cell damage is yet to be elucidated. Moreover, a fundamental question, what controls the T cell receptor (TCR)-pMHC tri-molecular complex interaction to productively stimulate a T cell and direct an antigen-specific T cell response in a certain direction is not well known and it may hold a key to block T1D development. Dr. Fite is interested in addressing the above immunological questions by applying nanomedicine and precision medicine concepts. His NanoImmunology laboratory research interests revolve around the following three interrelated basic and translational research areas.

1. Understanding the pMHC-TCR binding properties and modulate for effective immunotherapy.

Post-translational modifications of native antigens and multiple other mechanisms produce neoantigens with altered physicochemical properties from their native forms. T cells responding to these modified epitopes increase as the disease advances and play a key role in the development of T1D. We are keen to understand how change in the physicochemical nature of antigenic peptides and the microenvironment of pMHC-TCR interactions would influence T cell fate and TCR repertoire, impacting T1D.

2. Discovering novel nanodelivery modalities for antigens.

Nanomaterials are instrumental in designing antigen-specific immunotherapy that incorporates various components targeted to different pathways. In collaboration with Berkland Lab at Washington University, we recently used a soluble antigen array (SAgA) that carries multiple copies of antigenic peptides bound to hyaluronic acid polymer and showed that SAgAs, but not free peptides, efficiently block the development of T1D in non-obese diabetic (NOD) mice at equivalent doses. Corroborating the result, the phenotypes of antigen-specific T cells induced by SAgA and the free peptides were also distinct, uncovering the critical role of the nanodelivery modalities to achieve therapeutic efficacy. Our goal is to develop a next generation nanodelivery platform that encompasses an antigen-specific component and alteration of the inflammatory microenvironment of islets to achieve lasting immune tolerance in T1D.

3. Developing human immune system (HIS) mouse models for T1D.

From a translational and practical standpoint, HIS mouse models offer an excellent opportunity to study human immune cells in vivo. The mice used for HIS models have combinations of mutations that make them extremely immunodeficient and allow the engraftment of human CD34+ hematopoietic stem cells. However, the currently available HIS mice still have several limitations. They lack well-developed lymphoid tissues, which are critical for the initiation and coordination of immune responses and develop a poorly understood condition with features of autoimmunity and graft-versus-host disease. Therefore, we are interested in developing improved HIS mouse models that recapitulate human physiology to better understand the pathophysiology of T1D and predict human immune responses to immunotherapy.

1. Rebuma Firdessa-Fite*, Stephanie N Johnson, Martin A Leon, Ku A, Ocampo Gonzalez FA, Milner JD, Joshua O Sestak, Cory Berkland, Remi J Creusot*. Soluble antigen arrays provide increased efficacy and safety over free peptides for tolerogenic immunotherapy. Frontiers in Immunology (2024), 15, 1258369. https://doi.org/10.3389/fimmu.2024.1258369. *Corresponding author.

2. Rebuma Firdessa-Fite, Camillo Bechi Genzano, Remi J. Creusot. Epitope-based precision immunotherapy of Type 1 diabetes. Human Vaccines & Immunotherapeutics, 2154098 (2023). PMID: 36656048.

3. Jorge Postigo-Fernandez*, Rebuma Firdessa-Fite*, and Rémi J. Creusot.  Preclinical evaluation of a precision medicine approach to DNA vaccination in type 1 diabetes. Proceedings of the National Academy of Sciences 119 (15), e2110987119 (2022). PMID: 35385352. *Co-first authors and contributed equally.

4. Rebuma Firdessa-Fite, Stephanie N Johnson, Martin A Leon, Mohsen Khosravi-Maharlooei, Rocky L Baker, Joshua O Sestak, Cory Berkland, Remi J Creusot. Soluble Antigen Arrays Efficiently Deliver Peptides and Arrest Spontaneous Autoimmune Diabetes. Diabetes; 70(6):1334–1346 (2021). PMID: 33468513.

5. Rebuma Firdessa-Fite, Jorge Postigo-Fernandez,Valérie Toussaint-Moreau, Fabrice Stock, Alengo, Nyamay’Antu, Patrick Erbacher and Rémi J. Creusot.^. Promising non-viral vector for efficient and versatile delivery of mRNA for antigen-specific immunotherapy. Cell & Gene Therapy Insights 6(9), 1399–1409 (2020).

6. Rebuma Firdessa-Fite and Rémi J. Creusot^.  Nanoparticles versus dendritic cells as vehicles to deliver mRNA encoding multiple epitopes for immunotherapy. Molecular Therapy-Methods & Clinical Development 16, 50-62 (2020). PMID: 31871957.

7. Martin A. Leon*, Rebuma Firdessa-Fite*, Justin K. Ruffalo, Chad J. Pickens, Joshua O. Sestak, Remi J. Creusot, Cory Berkland. Soluble Antigen Arrays Displaying Mimotopes Direct the Response of Diabetogenic T cells. ACS Chemical Biology, 14 (7) 1436-1448 (2019). PMID: 31260253.  *Co-first authors and contributed equally.

8. Shamael R. Dastagir, Jorge Postigo-Fernandez, Chunliang Xu, James H. Stoeckle, Rebuma Firdessa-Fite and Rémi J. Creusot. Efficient Presentation of Multiple Endogenous Epitopes to Both CD4+ and CD8+ Diabetogenic T Cells for Tolerance, Molecular Therapy: Methods & Clinical Development 4: 27-38 (2017). PMID: 28344989.

9. Nor Fadhilah Kamaruzzaman, Rebuma Firdessa & Liam Good. Bactericidal effects of Polyhexamethylene Biguanide against intracellular Staphylococcus aureus EMRSA-15 and USA 300. Journal of Antimicrobial Chemotherapy, 71 (5),1252-1259 (2016). PMID: 26825118.

10. Rebuma Firdessa, Liam Good, Maria Cecilia Amstalden, Martina Schultheis, Bianca Röger, Nina Hecht, Tobias A. Oelschlaeger, Lorenz Meinel, Tessa Lühmann, Heidrun Moll: Pathogen and host directed antileishmanial effects mediated by polyhexanide (PHMB). PLOS Neglected Tropical Diseases, 9(10):e0004041(2015). PMID: 26431058.

11. Rebuma Firdessa, Tobias A. Oelschlaeger, Heidrun Moll: Multiple cellular uptake pathways of polystyrene nanoparticles and factors affecting the uptake: Relevance for drug delivery systems. European Journal of Cell Biology, 93(8-9):323-337 (2014). PMID: 25224362.