Targeted depletion of programmed death-1 positive cells, a method that not only stops autoimmune attack but also preserves adaptive immunity

点击翻译按钮获取中文摘要

Project Summary Autoimmune diseases (ADs) affect 50 million Americans and 12.5% of people worldwide, and for the vast majority of AD patients, there is no cure or effective prevention methods. The root cause of ADs is immune attack on self-tissues by auto-reactive effector lymphocytes and antibodies secreted by the lymphocytes. Therefore, lymphocyte suppression has been utilized as a strategy to ameliorate ADs. This strategy has yielded drugs that slow the progression of some ADs but do not prevent or cure ADs. Further, these drugs cause long-term immune deficiency and render AD patients susceptible to lethal opportunistic infections. One core reason for these deficiencies is the failure of current lymphocyte suppression drugs to focus on autoreactive effector cells. The drugs suppress and deplete native lymphocytes that do not contribute to ADs, which cause unnecessary and broad immune deficiency. Meanwhile, the current drugs fail to suppress all autoreactive effector lymphocytes: only B effector cells or only T effector cells are suppressed. To address this issue, we propose a novel lymphocyte suppression approach that encompasses all autoreactive effector cells but not naive cells. The approach utilizes the programmed death-1 receptor (PD-1) as a biomarker to identify, target and eliminate autoreactive effector cells. PD-1 is expressed on both B and T effector lymphocytes. Thus, it is possible to target all autoreactive effector lymphocytes using the PD-1 marker. More importantly, PD-1-positive (PD-1+) cells have been found to infiltrated inflamed tissues in ADs, and the infiltration is intensified while the ADs progress. An enhancement of the activity and amplification of PD-1+ cells by blocking PD-1 on these cells induced and aggravated ADs in animals and humans. On the contrary, our preliminary data showed that depletion of PD-1+ cells is very promising to treat autoimmune type-1 diabetes and chronic experimental autoimmune encephalomyelitis (EAE). On the hand, naive lymphocytes do not express PD-1, so depletion of PD-1+ cells will keep them intact. Taken together, we hypothesize that targeted depletion of PD-1-positive cells not only ameliorates in ADs but also preserves healthy immunity. To test this hypothesis, we generated an elegant protein molecule for in vivo PD-1+ cell depletion, aPD-1-ABD-PE. aPD-1-ABD-PE was designed to have three functional elements, an anti-PD-1 antibody (aPD-1) to target PD-1+ cells, an albumin-binding domain (ABD) to increase plasma presence of aPD-1-ABD-PE, and a Pseudomonas exotoxin (PE) to kill the cells that aPD-1-ABD-PE enters. aPD-1-ABD-PE has selective toxicity to PD-1+ cells. In this project, we will test the hypothesis through three specific aims: Aim 1: Characterize and prepare aPD-1-ABD-PE as a tool for targeted PD-1+ cell depletion; Aim 2: Establish that PD-1+ cell depletion ameliorates T1D, EAE, and SLE, three representative ADs; Aim 3: Establish that long-term PD-1+ cell depletion does not cause long-term immune deficiency. This project responds directly to the prominent need to improve the treatment for ADs, a priority area of study of the National Institute of Allergy and Infectious Diseases.