• Elected member in Alpha Omega Alpha (AOA) Medical Honor Society, Delta Zeta Chapter & Gold Humanism Honor Society by the Arnold P. Gold Foundation. Induction ceremony, Philadelphia, Pa., USA. March 22 (2023)
• Recipient 20-year service award by the Drexel University at the Service Recognition reception, Philadelphia, PA, USA. January 18 (2023)
• Received institutional pilot Open Access Publishing Fund ($2000) toward the article processing charges for the Drexel scholars (2022)
• Laboratory travel grant ($2500) by the American Association of Immunologists (AAI) to deliver a talk at Immunology 2022, Portland, OR, USA, May 6-10 (2022)
• Nomination for the Basic Science Research Award by the International Retrovirology Association (IRVA) (2022)

• Full member of the Immune Cell Regulation & Targeting (IRT) Program of Excellence at the Sidney Kimmel Cancer Center, TJU, Philadelphia, Pa. (2022–present)
• American Society for Exosomes and Microvesicles (ASEMV) (2020–present)
• Elected member of the American Society of Hematology (ASH) (2019–present)
• International Retrovirology Association (IRVA) (2014–present)
• American Asian Pacific Islander (AAPI), a National Institute of Drugs Abuse (NIDA/NIH) supported group (2012–present)
• National Association of Professional Women (NAPW) (2010–present)
• International Society for Dendritic Cell & Vaccine Science, Life Member (2010–present)
• Society for Leukocyte Biology, USA (2009–present)
• Women in Neurovirology Committee, USA (2009–present)
• American Society of Microbiology (ASM) (2002–present)
• International Society for Neurovirology (ISNV), USA (2003–present)
• American Society of Virology (ASV) (2006–present)
• International Society for Neuroimmunology (ISNI), USA (2006–present)
• The American Association of Immunologists (AAI) (2009–present)
• Society on NeuroImmune Pharmacology (SNIP), USA (2009–present)

Graduate students: Julie Joseph, MS; Nicholas Edouard and Grace Sandel

Research staff: Adjei Keziah

Project #1: Targeting MEF-2 signaling as a therapeutic strategy for T-cell leukemia/lymphoma via antisense transcriptional control.

About 15 million people are infected with HTLV-1 and many millions with HTLV-2 worldwide. The surprisingly recent detection of high prevalence rates among the indigenous people of central Australia has raised a new alarm and heightened attention to HTLV infection and associated malignancies termed ATLL (adult T-cell leukemia/lymphoma), emphasizing the important public health issues that have yet to be addressed. This proposal will investigate the role of a novel target MEF-2 (myocyte enhancer factor 2) in promoting ATLL pathogenesis and elucidate the mechanism by which this protein influence ATL severity and chemoresistance, providing the opportunity to develop efficacious therapeutic interventions.

HTLV-1, the first retrovirus identified to directly cause human cancer is the most carcinogenic human oncovirus and does not currently have an effective treatment or vaccine. Our ongoing studies are a relevant continuation of our original findings and will reveal new information with respect to HTLV-1 antisense transcription and viral oncogenesis while moving forward the field of retroviral (e.g. HIV-1, HTLV-2, etc.) antisense transcription.

Project #2: The highly enriched c-type lectins on dendritic cells provide potential immunotherapeutic strategy to ameliorate neuroinflammatory diseases.

The seminal contribution of our research lies in bridging two important fields of neuroscience and immunology while strengthening DCs’ presence and functions within CNS. This is by means of our original work providing direct evidence for the ability of circulating DCs to migrate across the inflamed BBB during an active ongoing neuroinflammatory condition (EAE) by live intravital videomicroscopy. This was further substantiated by a variety of non-invasive imaging tools such as NIRF, SPECT-CT, and PET-based in vivo imaging (Fig. 1).

The mechanism by which DCs are recruited across the BBB during neuroinflammation has been the least explored amongst all leukocytes. For cells of myeloid origin, lectins and integrins are two major groups of receptors involved in trafficking cascade. While integrins function at the level of adhesion, the importance of lectins (highly enriched on DCs) remains unknown. We have identified functions of one C-type lectin receptor (mainly CLEC12A) in facilitating DCs binding and transmigration across the BBB in response to CCL2 chemotaxis. Specific antibody blocking of CLEC12A significantly ameliorated the course of experimental autoimmune encephalomyelitis in mice through an inhibition of myeloid cell infiltration into the brain and spinal cord. These studies revealed the utility of a DC-specific mechanism in designing new therapeutics for MS. We now wish to proceed with pre-clinical efficacy and toxicity testing followed by phase I clinical trial for CLEC12A blockade as potential new therapy for the management of MS.

Figure 1. NIRF and SPECT-CT imaging of leukocyte presence in EAE CNS lesions. Mice were injected with either (1) anti-CD11c Ab-IRDye800, (2) anti-CD11c Ab-IRDye800+anti-CD3 Ab-IRDye680 (T cells) or (3) anti-CD11c Ab-IRDye800+anti-MBP Ab-IRDye680 on EAE day 14 and imaged 48 h post-antibody using ex vivo NIRF imaging to validate the ability to track cells to EAE lesions. A) Anti-CD11c antibody only (green) signal from DCs in a mouse with severe EAE. B) Mouse with moderate EAE score shows signal from both CD11c+ DCs (green) and CD3+ T cells (red). C) Mouse exhibiting mild EAE shows a high degree of co-localization between CD11c+ DCs and MBP signal. D) 3D rendered view of whole-body α-CD68 Ab distribution at 48h post-tracer showing mostly thyroid, stomach, spleen, and gut. E) An enhanced view of tracer uptake in thoracic spine. Red arrows denote spine uptake.

Project #3: Exosomes and ESCRT machinery in Neuroinflammation Caused by Retrovirus Infection.

Exosomes are small extracellular vesicles (sEVs, 50-200nm) that are involved in complex intercellular communication via diverse cargo consisting of lipids, nucleic acids, and proteins. Exosomes originate from the multivesicular bodies (MVBs), transported/fused with the membrane, and released into the extracellular space depending upon physiological condition and the ESCRT (endosomal sorting complexes required for transport) machinery. The ESCRT machinery is made of peripheral protein complexes (ESCRT-0, -I, -II, -III VPS4-VTA1, and ALIX homodimer) that are successively recruited by late endosomes to form the MVB. Exosomes play important roles in cancer, virus infection and neurological diseases. Infection with human T-cell leukemia virus type 1 (HTLV-1, the very first human retrovirus identified) causes HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), with pathological parallels to both Multiple Sclerosis and HIV-associated neurocognitive disorder (HAND). Infection is carried to the central nervous system (CNS) by infected CD4 T cells and chronically activated CD8 T cells that are primed against HTLV-1 but can also recognize myelin antigens (molecular mimicry) creating an autoimmune condition in the CNS. This complex neuroimmune pathogenesis is incompletely understood, and there is no effective treatment, vaccine or cure available for HAM/TSP.

Over the years, our laboratory has made tremendous efforts in understanding the root cause of neuroinflammation and observed that T cells from HAM/TSP patients spontaneously proliferate and consistently express high levels of negative checkpoint receptors (NCRs) such as PD-1/PD-L1, LAG-3, Tim-3 and TIGIT. Elevated presence of these immune checkpoint (ICP) mediators inhibits cytolytic activity of HTLV-specific T cells contributing to high proviral load and chronic antigen exposure with viral proteins, Tax and HBZ. Interestingly, these proteins along with unique cytokines and NCRs are released in soluble and exosomal forms in HAM/TSP sera and patient derived infected CD4 T cells (preliminary data). Typically, the ESCRT machinery is involved in the inward abscission of membranes, and enveloped viruses such as HIV-1 reprograms this machinery to facilitate viral budding thru “reverse topology.” More so, ESCRT proteins were enriched in PD-L1’s proximal proteome, and EV biogenesis was affected by anti-PD-L1 treatment, suggesting a link between ICPs and ESCRT. We hypothesize that ESCRT machinery play critical role in release of exosomes from HTLV-infected cells with specific cargo that contribute to neuroinflammation via viral RNA/protein, proinflammatory cytokines, and co-inhibitory receptors. To test this, a CRISPR-based library screen for membrane trafficking genes will be employed, and gRNAs will be selected for exosome-associated disease determinants such as viral mRNAs/proteins, cytokines and NCRs. The in vivo evaluation of most critical ESCRT member(s) will be performed in Wistar rat model of HAM/TSP with knockout. These innovative studies will establish role of exosomes and soluble checkpoint mediators in a neuroinflammatory disease caused by retroviral infection providing new clues for future therapeutic development.

Videos

Initial contact of immature dendritic cells(DCs) and LPS-matured DCs by rolling or capturing with the inflamed spinal cord microvasculature in SJL mice with EAE.

Adhesion of immature DCs and LPS-matured DCs to the inflamed spinal cord white matter microvasculature in SJL mice with EAE.

Selected Publications
View all of Dr. Jain's publications in PubMed

“Apigenin improves cytotoxicity of antiretroviral drugs against HTLV-1 infected cells through the modulation of AhR signaling”
Sales, D., Lin, E., Stoffel, V., Dickson, S., Khan, Z. K., Beld, J., and P. Jain
NeuroImmune Pharmacology and Therapeutics (NIPT), 1-14 (2023)

“TLR9 signaling activation via direct ligation and its functional consequences in CD4+T cells”
Sharma, R., Sharma, J., Kumar, R., Badal, D., Pattekar, A., Sehgal, S., Gupta, A., Jain, P., and Naresh Sachdeva
Scandinavian Journal of Immunology, e13214:1-18 (2022)

“Regulation of Human T-cell leukemia virus-1 antisense promoter by Myocyte Enhancer factor-2C in the pathogenesis of Adult T-cell leukemia and lymphoma”
Madugula, K., Joseph, J., Demarino, C., Ginwala, R., Teixeira, V, Khan, Z. K., Sales, D., Kashanchi, F., Rushing, A. W., Lemasson, I., Harhaj, E. W., Janakiram, M., Ye, B., P. Jain
Haematologica, 107:2928-2943 (2022)

“Phenotypic and Functional Analyses Guiding Combination Immune Checkpoint Immunotherapy Strategies in Chronic HTLV-1 Infection”
Clements, D., Crumley, B., Chew, G., Davis, E., Bruhn, R., Murphy, E., Ndhlovu, L., and P. Jain
Frontiers in Immunology, 12:1-14 (Article 608890) (2021)

“Risk Factors Associated with the Clinical Outcomes of COVID‐19 and Its Variants in the Context of Cytokine Storm and Therapeutics/Vaccine Development Challenges”
Hahn J, Tipparaju P, Mulhurkar T, Lin E, Mischley, V., Kulkarni, R., Bolton, A., Byrareddy, S., and P. Jain
Vaccines, 9: 938-969. https://doi.org/10.3390/vaccines9080938 (2021)

“Apigenin modulates dendritic cell activities and curb inflammation via RelB inhibition in the context of neuroinflammatory diseases”
Ginwala, R., Bhavsar, R. Moore, P., Bernui, M., Singh, Bearoff, F., Nagarkatti, M., Z. K. Khan, and P. Jain
Journal of Neuroimmune Pharmacology, 16:403-424 (2021)

“In vivo and in vitro immunogenicity of novel MHC class I presented epitopes to confer protective immunity against chronic HTLV-1 infection”
Mulherkar, R., Karabudak, A., Ginwala, R., Huang, X., Rowan, A., Philip, R., Murphy, E., Clements, D., Ndhlovu, L., Khan, Z. K., and P. Jain
Vaccine, 36: 5046-5057 (2018)

“FDC-TFH Interactions within CNS Draining Cervical Lymph Nodes of SIV-Infected Rhesus Macaques”
Dave, R., Sharma, R., Muir, R., Haddad, E., Gumber, S., Villinger, F., Nehra, A., Khan, Z. K., Wigdahl, B., Ansari, A., Byrareddy, S., and P. Jain
Journal of Neuroimmune Pharmacology, 13(2): 204-218 (2018)

“Stromal cyclin D1 promotes heterotypic immune signaling and breast cancer growth”
Pestell, T., Jiao, X., Yu, Z., Kumar, M., Peck, A., Prisco, M., Deng, S., Li, Z., Ertel, A., Casimiro, M., Ju., X., Rocco, A., Sante, G., Katiyar, S., Shupp, A., Lisanti, M., Jain, P., Wu, K., Rui, H., Hooper, D., Yu, Z., Goldman, A., Speicher, D., and R. Pestell
Oncotarget, 8: 81754-81775 (2017)

“Antibody blockade of CLEC12A delays the course of EAE and attenuates disease severity by impairing myeloid cell CNS infiltration and restoring positive immunity”
Sagar, D., Singh, N., Ginwala, R., Huang, X., Philip, R., Nagarkatti, M., Nagarkatti, P., Neumann, K., Ruland, J., Andrews, A., Remirez, S., Khan, Z. K., and P. Jain
Scientific Reports, 7(1): 2707-23 (2017)

Book

Advanced Concepts in Human Immunology: Prospects for Disease Control
P. Jain (Chief Editor) and L. Ndhlovu (Co-editor)
Springer International Publishing; 2020. DOI:10.1007/978-3-030-33946-3_1 ISBN: 9783030339456(1)

Book Chapters

“Immune Mechanisms, Pathology, and Management of Allergic Ocular Diseases”
Chigbu, D., Jain, P., and Z. K. Khan
In the Edited Book (P. Jain and L. Ndhlovu, editors) Advanced Concepts in Human Immunology: Prospects for Disease Control. Springer International Publishing. DOI:10.1007/978-3-030-33946-3_1 ISBN: 9783030339456(1) (2020)

“Transgenic Animals in Research and Industry”
Masih, S., Kamal, S., Jain, P., and Z. K. Khan
Chapter 21, pp. 407-423. Elsevier Science Publications, edited book Animal Biotechnology: Models in Discovery and Translation, 2nd Advance Edition (2020)

“Acute and Chronic Human Viral Infections: Host-Pathogen Interaction and Therapeutics”
Hoffman, M., Chigbu, D., Crumley, B., Sharma, R., Pustylnikov, S., Crilley, T., Loonawat, R., Joseph, J., Sales, D., Wilson, D., Ginwala, R., and P. Jain
In the Edited Book (P. Jain and L. Ndhlovu, editors) Advanced Concepts in Human Immunology: Prospects for Disease Control. Springer International Publishing. DOI:10.1007/978-3-030-33946-3_1 ISBN: 9783030339456(1) (2020)

Editorial and Commentary

“Apigenin as anti-TNF alpha agent. Invited commentary/short communication for Scientific Archives”
Mulherkar, T., Ginwala, R., Khan, Z. K., and P. Jain
Journal of AIDS and HIV Treatment, 3(3): 49-53 (2021)

“Functional meningeal lymphatics and cerebrospinal fluid outflow”
Dave, R., Jain, P., and S. Byrareddy
Commentary in Journal of Neuroimmune Pharmacology, 13(2): 123-125 (2018)

“Update on Gender Equity in Immunology, 2001 to 2016”
Shapiro, V., Kovats, S., Parent, M., Gaffen, S., Hedrick, C. Jain, P., Denzin, L., Raghavan, M., and R. Stephens
Journal of Immunology, 197: 3751-3753 (2016)

“HTLV-1 infection and its associated diseases”
Saito, M., Jain, P., Tsukasaki, K., and C. R. M. Bangham
Leukemia Research and Treatment (2012)

“MEF-2C Drives T-cell Proliferation from the Antisense Promoter of HTLV-1 via b-zip protein, Menin and JunD Leading to ATLL”
Invited talk at the 7th International Conference on Cancer Research and Drug Development (CRD 2022), October 24-27, Baltimore, Md. (October 26, 2022)

“Mechanistic and therapeutic of retroviral and neuroinflammatory diseases”
Invited seminar at the Hunter College, NYU, New York, N.Y. (October 21, 2022)

“Discovery of a new target for ATLL, mechanistic studies & pharmacological intervention”
Invited talk at the SKCC Hematologic malignancies working group. Thomas Jefferson University, Philadelphia, Pa., (September 27, 2022)

“Mechanistic and therapeutic of retroviral diseases and associated neuroinflammation”
Invited talk in the Quantitative Bioscience division of Merck, Lansdale, Pa. (June 29, 2022)

“Nutraceutical Apigenin regulates DC function in a RelB-dependent manner during neuroinflammation”
Invited talk in the session - Neuronal and central nervous system immunity. Immunology 2022, Portland, May 6-10, May 8 (2022)