The low-toxicity versions of LPS, MPL® adjuvant and RC529, are efficient adjuvants for CD4+ T cells

Abstract

Lipopolysaccharide (LPS) has long been known to enhance innate and adaptive immune responses; however, its extreme toxicity precludes its use in clinical settings. The combined toxicity and adjuvanticity of LPS have contributed to the view that immunological adjuvants need to be highly inflammatory to be maximally effective. Here, we compared the effects of LPS with its less-toxic derivatives, monophosphoryl lipid A (MPL) and a chemical mimetic, RC529, on CD4+ T cell clonal expansion, long-term survival, and T helper cell type 1 (Th1) differentiation. We found that LPS, MPL, and RC529 had similar effects on CD4+ T cell clonal expansion, cell division, and ex vivo survival. Analysis of the ability of activated CD4+ T cells to produce interferon-gamma following a 21-day immunization and challenge protocol with LPS and MPL resulted in similar Th1 differentiation. In contrast, we found that LPS was more effective in promoting long-term CD4+ T cell responses, as we recovered nearly sixfold more cells following immunization/challenge as compared with treatment with MPL. Our results indicate that low-inflammation adjuvants, such as MPL and RC529, are capable of enhancing short-term CD4+ T cell clonal expansion and Th1 differentiation, but inflammatory signaling aids in the long-term retention of antigen-specific T cells.

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

“…Although TLR agonists have often been used in experimental and clinical studies as an immune adjuvant [27], many are associated with significant side effects or toxicity [37,38]. FimH represents a recently discovered TLR4 ligand with a great potential to be a safe and effective immune modulator, particularly amenable for mucosal application based on its selective effect on APCs [39].…”

Potential adjuvantic properties of innate immune stimuli

“…55 For instance, monophosphoryl lipid A induces dendritic cell maturation, [56][57][58][59][60] upregulates MHC Class II molecules and CD80 and CD86, [61][62][63] and also indirectly reduces the threshold for activation of T H 1 cells. [64][65][66][67][68][69] …”

Selective Activation of the p38 MAPK Pathway by Synthetic Monophosphoryl Lipid A

“…However, strong inflammatory responses that can be caused by these compounds may limit their use in humans, especially in the context of prophylactic immunization of healthy individuals. One exception is the TLR4 agonist monophosphoryl lipid A (MPLA), a low toxicity derivative of lipopolysaccharide (LPS) that enhances T cell priming and antibody responses against antigens without causing excessive inflammatory side effects (1)(2)(3)(4). We reported previously that the beneficial, immunostimulatory activities of MPLA are correlated with its ability to stimulate TLR4 preferentially through one of its two major signaling pathways, the TRIF adapter pathway (3).…”