Ultra-Low Dose Cytokines in Rheumatoid Arthritis, Three Birds with One Stone as the Rationale of the 2LARTH® Micro-Immunotherapy Treatment

Abstract

Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are two cytokines involved in the perpetuation of the chronic inflammation state characterizing rheumatoid arthritis (RA). Significant advances in the treatment of this pathology have been made over the past ten years, partially through the development of anti-TNF and anti-IL-1 therapies. However, major side effects still persist and new alternative therapies should be considered. The formulation of the micro-immunotherapy medicine (MIM) 2LARTH^® uses ultra-low doses (ULD) of TNF-α, IL-1β, and IL-2, in association with other immune factors, to gently restore the body's homeostasis. The first part of this review aims at delineating the pivotal roles played by IL-1β and TNF-α in RA physiopathology, leading to the development of anti-TNF and anti-IL-1 therapeutic agents. In a second part, an emphasis will be made on explaining the rationale of using multiple therapeutic targets, including both IL-1β and TNF-α in 2LARTH^® medicine. Particular attention will be paid to the ULD of those two main pro-inflammatory factors in order to counteract their overexpression through the lens of their molecular implication in RA pathogenesis.

Keywords: IL-1β; TNF-α; anti-inflammatory medicines; chronic inflammation; hormesis; inflammatory cytokines; micro-immunotherapy; rheumatoid arthritis; ultra-low doses.

Figure 1

Schematic representation of the different levels of IL-1β’s implication in the pathogenesis of rheumatoid arthritis (RA). IL-1R1: Interleukin-1 type-I receptor; IL-1RAcP: IL-1 receptor accessory protein; MAPK: Mitogen-activated protein kinase; MMP: Matrix metalloproteinase; MyD88: Myeloid and differentiation primary response 88; NF-κB: Nuclear factor-κB; PGE2: Prostaglandin E2; TIR: Toll-IL-1 receptor.

Figure 2

Schematic representation of the different levels of TNF-α’s implication in the pathogenesis of rheumatoid arthritis (RA): IL-1β: Interleukin-1β; IκB: Inhibitor of nuclear factor-κB; GM-CSF: Granulocyte-macrophage colony-stimulating factor; MAPK: Mitogen-activated protein kinase; MCP1: Monocyte chemoattractant protein-1; MIP1α: Macrophage inflammatory protein-1 alpha; MMP: Matrix metalloproteinase; NF-κB: Nuclear factor-κB; RANKL: Receptor activator of nuclear factor-κB ligand; SNP: Single nucleotide polymorphism; TIR: Toll-IL-1 receptor; TNFRI: TNF receptor type 1; TRAF1: TNF receptor-associated factor; TRAF-C5: TNF receptor-associated factor 1 and complement component 5; VEGF: Vascular endothelial growth factor.

Figure 3

Schematic representation of (A) therapeutic targets of current treatments of RA and (B) the putative targets of 2LARTH^®: IL-1R1: Interleukin-1 type-I receptor; IL-1RAcP: IL-1 receptor accessory protein; MAPK: Mitogen-activated protein kinase; MyD88: Myeloid and differentiation primary response 88; NF-κB: Nuclear factor-κB; TIR: Toll-IL-1 receptor; TNFRI: TNF receptor type 1; TRAF1: TNF receptor-associated factor 1; ULD: Ultra-low dose. Red plain lines represent inhibition mechanisms, red dotted lines represent modulatory mechanisms.

Figure 4

Schematic representation of the multi-targets actions of 2LARTH^® within the cells of the synovial niche in rheumatoid arthritis (RA): HLA: Human leukocyte antigen; IL-1R: Interleukin-1 receptor; IL-2R: Interleukin-2 receptor; SNA^®: Specific nucleic acid; TNFR: TNF receptor; ULD: Ultra-low dose.