drs j and g

McGowan Institute for Regenerative Medicine affiliated faculty members Jelena Janjic, PhD, Associate Professor of Pharmaceutics in the Graduate School of Pharmaceutical Sciences and Mylan School of Pharmacy at Duquesne University and the Founder and Co-Director of the Chronic Pain Research Consortium at Duquesne, and Vijay Gorantla, MD, PhD, Associate Professor of Surgery, Ophthalmology and Bioengineering at the Wake Forest School of Medicine, will serve as co-principal investigators on a recent grant funded through the Department of Defense Congressionally Directed Medical Research Program. Dr. T. Kevin Hitchens, Director of Preclinical MRI, UPMC Hillman Cancer Center; Director of the Animal Imaging Center, University of Pittsburgh School of Medicine; and Research Associate Professor of Neurobiology, University of Pittsburgh is also a co-principal investigator. The award of $1.5M over three years  from the Reconstruction Transplant Research Program will focus on the project entitled “Nanoimaging for Noninvasive Monitoring of Donor and Recipient Immune System Contribution to Acute and Chronic Rejection in VCA.”  The abstract of this work follows:

“Despite two decades of experience with clinical vascularized composite allotransplantation (VCA), the sensitivity and specificity of skin rash as a marker of acute rejection (AR) and the sampling error on skin biopsies remains unknown. The extent and intensity of skin involvement by clinically apparent AR (e.g., papular or erythematous rash) is usually the initial driver of management. One of the key reasons for treatment failure and recurrent rejection in VCA is lack of non-invasive deep tissue-penetrating imaging modalities that can provide the clinician true state of the graft during the course of treatment and lifetime of the graft. Many of these cases with chronic rejection (CR) have been associated with medication non-compliance (NC) that causes wide fluctuations of systemic drug levels with periodic or persistent under-immunosuppression, leading to smoldering immune responses in the graft. Thus, missed interpretation or underreporting of CR (as current Banff criteria do not include CR) across all VCA may be more prevalent than assumed, given the constraints of access to protocol/for-cause deep tissue biopsies. There is thus an imminent need for non-invasive tools that enable reliable and reproducible, quantitative, and objective diagnosis and monitoring of rejection in deep graft tissues otherwise inaccessible by skin biopsy.

“Novel nanoprobes capable of immunolabeling multiple cell populations in vivo can shed critical insights into the dynamics, kinetics, intensity, and spatial patterns or progression of cellular VCA rejection across deep and superficial tissues, as well as objectively quantify responsiveness or resistance of rejection to immunosuppressive therapy. The proposed nanoimaging probes will be produced by GMP-scalable methodologies using only materials already deemed safe for use in humans. Proposed nanoimaging agents are designed for safe and effective immune cell tracking in small and large animals and, as such, are readily translatable to clinical VCA. Our proposed technology meets the needs of VCA recipients and clinicians for accurate, non-invasive diagnosis and monitoring of rejection in superficial and deep tissues, assessment of therapeutic response, and, consequently, true treatment personalization and assessment of patient compliance.

“We hypothesize that our proposed cellular nanoimaging biomarker approach using multispectral probes will noninvasively detect, quantify, and monitor macrophage-driven immune processes in superficial and deep tissues of VCA during AR or CR and assess therapeutic efficacy and treatment response to immunosuppressive interventions. Proposed tools also offer unbiased quantitative patient-reporting independent compliance assessment. To test this hypothesis, in Aim 1, we will manufacture and validate in small animals multispectral and multimodal nanoimaging agents. In Aim 2, we will test these agents in rodent models of VCA to establish immune cell distribution patterns in acute and chronic rejection and, in Aim 3, we will validate this technology as a therapeutic response biomarker in acute and chronic rejection in a non-human primate VCA model. Additionally, we will evaluate in a non-human primate model, for the first time, nanoimaging methods as unbiased biomarkers for non-invasive monitoring of patient compliance.

“Proposed strategies are an unprecedented advancement in VCA, where standard-of-care diagnosis and management are guided by invasive graft monitoring and where for-cause superficial skin biopsies are not reliable indicators of deeper tissue rejection. Presented nanoimaging methods can potentially provide unique first insights into the cellular dynamics of deep tissue rejection, its spatiotemporal association with skin AR, and overall therapeutic responses of superficial versus deep tissue rejection in VCA. Such noninvasive immune surveillance can facilitate precise immunosuppression management in Service members as well as civilians receiving VCA for devastating tissue loss, enabling optimization/personalization of immunosuppression as well as unbiased monitoring of patient adherence to medications. The long-term vision of this technology lies in its scope and scalability to wider populations beyond combat/civilian subjects seeking VCA, such as immunotherapy monitoring, inflammatory diseases (IBD, RA, lupus), and autoimmune diseases.”

Congratulations, Drs. Janjic and Gorantla!