Gene Therapy Induces Antigen-Specific Tolerance in Experimental Collagen-Induced Arthritis

Abstract

Here, we investigate induction of immunological tolerance by lentiviral based gene therapy in a mouse model of rheumatoid arthritis, collagen II-induced arthritis (CIA). Targeting the expression of the collagen type II (CII) to antigen presenting cells (APCs) induced antigen-specific tolerance, where only 5% of the mice developed arthritis as compared with 95% of the control mice. In the CII-tolerized mice, the proportion of Tregs as well as mRNA expression of SOCS1 (suppressors of cytokine signaling 1) increased at day 3 after CII immunization. Transfer of B cells or non-B cell APC, as well as T cells, from tolerized to naïve mice all mediated a certain degree of tolerance. Thus, sustainable tolerance is established very early during the course of arthritis and is mediated by both B and non-B cells as APCs. This novel approach for inducing tolerance to disease specific antigens can be used for studying tolerance mechanisms, not only in CIA but also in other autoimmune diseases.

Collagen II-primed Foxp3 Transduced T Cells Ameliorate Collagen-induced Arthritis in Rats: The Effect of Antigenic Priming on T Regulatory Cell Function

“…A critical role for anti-CII specific IgG for the development of CIA has been demonstrated by previous studies 1 and it has been shown that the lgG2a subclass is a major produced antibody against CII. 36 In addition, some adoptive T cell therapy works shown a decrease in the levels of hallmarks CII-specific IgG 14 and IgG2a.…”

“…Rheumatoid arthritis (RA) is a chronic inflammatory joint disease 1 which is characterized by proliferative synovitis of diarthrodial joints that leads to articular cartilage and bone destruction 2 RA is widely believed to be an autoimmune disorder where dysregulation of self-tolerance mechanisms leads to generation of auto reactive lymphocytes which target tissue-specific auto antigens derived from joint. 3 Similar to most autoimmune disorders, exact tissuespecific self-antigens and also precise pathogenic events leading to RA are not known.…”

Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis

“…Presentation of the immunodominant T-cell epitope in CII, the CII-peptide amino acids 259–270, on MHC II A q is important for both disease development [ 23 , 24 ] and tolerance [ 16 , 17 , 25 ]. We have shown previously that adoptive transfer of B cells presenting the CII - peptide on MHC II A q induces partial tolerance to CIA [ 19 ]. In these experiments we used the LNT-SFFV-CII/CLIP lentiviral vectors, where expression of CII was driven by the general SFFV promoter (Additional file 3 : Figure S3B).…”

“…We have shown previously that administration of lentiviral particles which results in expression of the CII-peptide on all APCs induces tolerance [ 17 – 19 ]. Here, we use our lentiviral system to target expression of the CII-peptide specifically on B cells, using a B-cell specific Igk promoter [ 20 ].…”

Vitamin D Deficiency and Rheumatoid Arthritis

“…Background RA treatment usually consists of combined therapies that suppress the entire immune response, leading to increased susceptibility to a plethora of infections. In this sense, many efforts are made to develop more specific immunomodulatory strategies as, for example, the induction of antigen-specific tolerance [86][87][88]. Self-tolerance can be induced by different procedures such as self-antigen administration via tolerogenic routes (oral mucosa, for example), concomitant blocking of co-stimulatory molecules, or self-antigen targeting to resting antigen-presenting cells, such as DCs [89].…”