The work my laboratory does in the Division of Surgical Research/ Department of Surgery, Lifespan-R.I. Hospital has centered on developing a better understanding of what the mechanisms of severe traumatic shock, injury and/or sepsis are and what impact they may have on the patient that lead to increasing their susceptibility to subsequent infection and multiple organ failure. Importantly, we’ve tried to do this not only by the application of what we think are valuable pre-clinical models, but also through collaborative partnerships with clinician scientists here at Lifespan-R.I. Hospital and the world that can translate the significance of our bench-side observations back to the critically ill patient. Excitingly, while working for years on defining numerous defects of components of patient’s immune responsiveness caused by shock and/or sepsis, we’ve uncovered novel role(s) for a number of the cell-associated regulatory receptors of the B7-family, i.e., Programmed Cell Death Receptor-1 [PD-1], B-/T-Lymphocyte Attenuator [BTLA], recently, V-domain Immunoglobulin Suppressor of T cell Activation [VISTA, a.k.a., B7-H5, PD-1H] and their respective cell surface ligands; popularly referred to as checkpoint proteins.
The primary role of these checkpoint receptors is understood to be critical to diseases of autoimmunity, viral infection, cancer and/or transplant (diseases of failed adaptive [lymphoid] immunity). Thus, as the historic perspective of this field is that the pathophysiology of the immune response of the injured and/or septic individual is one of dysregulated phagocyte driven inflammation, these checkpoint proteins should be irrelevant to the development of the critically ill patient’s morbid state. What our and other’s data tell us is that a number of these receptors have far more diverse cell/organ targets than was initially appreciated. While it’s clear that lymphocyte checkpoint protein expression has a role in the septic process, the novel observations we’ve made are that they have unanticipated effects on phagocytes, innate regulatory lymphoid cells, non-immune cells (i.e., endothelial cells, epithelial cells, etc.), and they appear to be strong inducers of immune/organ dysfunction in the injured and/or septic patient. Importantly, inhibitors (neutralizing/blocking monoclonal antibodies) of some of these checkpoint proteins have recently been approved for clinical use for the treatment of select cancers, precipitating their compassionate use in fungal sepsis and in a phase 1b clinical trial showing that antibodies against a ligand of PD-1 can be safely administered in the critically ill. However, to apply these agents well, either alone or in drug combination, in the critically ill patient, we need to identify when and what population would most benefit from receiving these agents, guided by the checkpoint protein blood or leukocyte levels. To do this, it’s critical that we understand not only what regulates expression of these checkpoint proteins and/or their ligands in injury/shock and/or sepsis, but what this means patho-physiologically; especially in varied populations, i.e., adult, neonate/infant or in the aged.