No abstract

Safe, effective, antigen-specific therapy for rheumatoid arthritis (RA) remains an elusive clinical goal with a few lasting, viable options on the horizon. Existing therapeutic interventions are indiscriminate and inconsistently immunosuppressive, often leaving patients susceptible to infection. Herein, we investigate the use of a dual-sized, microparticle “regulatory vaccine” (REGvac) that passively targets dendritic cells for antigen-specific biomaterial-based immunotherapy of RA. This REGvac employs poly­(d,l-lactic-co-glycolic-acid) (PLGA) microparticles (MPs) encapsulating (i) a dendritic cell chemoattractant, (ii) potent immunosuppressive molecules, (iii) and an RA-relevant autoantigen to provide a multifaceted approach for the treatment of collagen-induced arthritis (CIA), the primary mouse model of RA. Subcutaneous administrations of the REGvac after mice had developed moderate clinical symptoms markedly diminished overt inflammation in the paws, halted cartilage degradation, and restored gait parameters within 56 days after initial treatment. Positron emission tomography imaging corroborated reduction of inflammation in the paws of REGvac-treated mice. In-depth immunological assessments showed a decreased expression of CD80, CD86, and MHC II on CD11c+ dendritic cells in joint-associated lymph nodes. Further, we observed significant increases in conventional regulatory CD25+FOXP3+ T cells, as well as programmed cell death protein-1 (PD-1)-expressing CD4+ T cells in joint-proximal lymph nodes and the spleen. Real-time PCR analysis of joint tissues from treated mice revealed significant decreases in inflammatory cytokine expression (IL-6), while IL-10 mRNA levels were significantly increased. These observations strongly hint toward the induction of multiple tolerogenic mechanisms by administration of this MP regulatory vaccine. With regards to antigen specificity, ex vivo antigen recall assays revealed a lack of response to collagen by CD4+ T cells from the popliteal and inguinal lymph nodes of REGvac-treated mice, contrasting with the proliferative response of CD4+ T cells from CIA+ mice. Taken altogether, our results strongly support the application of this MP regulatory vaccine as a potent, biomaterial-based, antigen-specific therapy for RA.

Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative disorder that affects motor neurons in the brain and spinal cord, causing progressive loss of voluntary muscle control 1,2 . ALS heterogeneity includes the age of manifestation, the rate of progression, and the anatomical sites of symptom onset. In addition, disease-causing mutations in specific genes have been identified and are used to catalog different subtypes of ALS 3 . Interestingly, several ALS-associated genes have been shown to affect immune functions, and a variety of aberrant inflammatory events have been reported in patients and mouse models 4-11 , suggesting that specific immune features can also account for ALS heterogeneity. ALS4 is characterized by juvenile-onset and slow progression 12 . After experiencing mild symptoms during their childhood, ALS4 patients show motor difficulties by their 30s, and most of them require walkers or wheelchairs by their 50s. ALS4 is caused by dominant mutations in the gene SETX. Using Setx knock-in (KI) mice carrying the ALS4 causative L389S mutation, we discovered an immunological signature consisting of clonally activated CD8 T cells specifically in the central nervous system and blood of KI animals. Expansion of antigen-specific CD8 T cells mirrors disease progression. Bone marrow transplantation experiments indicate an essential role of the immune system in ALS4 neurodegeneration. Furthermore, we found that clonally expanded CD8 T cells circulate in the peripheral blood of ALS4 patients. Our results provide evidence of an antigen-specific CD8 T cell response linked to ALS4, and can serve not only to unravel specific disease mechanisms, but as a potential biomarker of disease activity. MainALS4 is caused by heterozygous mutation in the SETX gene, which encodes for the Senataxin protein, an ubiquitously expressed nuclear ATP-dependent DNA/RNA helicase [13][14][15][16] . Senataxin can resolve DNA/RNA hybrids and regulate RNA metabolism 14,17 . Also, we demonstrated that lack of Senataxin results in increased type I interferon (IFN-I) responses upon infection 16 ,

Human T cells have a diverse T-cell receptor (TCR) repertoire that endows them with the ability to identify and defend against a broad spectrum of antigens. The universe of possible antigens that T cells may encounter, however, is even larger. To effectively surveil such a vast universe, the T-cell repertoire must adopt a high degree of crossreactivity. Likewise, antigen-specific and cross-reactive T-cell responses play pivotal roles in both protective and pathological immune responses in numerous diseases. In this review, we explore the implications of these antigen-driven T-cell responses, with a particular focus on CD8+ T cells, using infection, neurodegeneration, and cancer as examples. We also summarize recent technological advances that facilitate highthroughput profiling of antigen-specific and cross-reactive T-cell responses experimentally, as well as computational biology approaches that predict these interactions.