Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype–positive rheumatoid arthritis patients

Abstract

In animals, immunomodulatory dendritic cells (DCs) exposed to autoantigen can suppress experimental arthritis in an antigen-specific manner. In rheumatoid arthritis (RA), disease-specific anti-citrullinated peptide autoantibodies (ACPA or anti-CCP) are found in the serum of about 70% of RA patients and are strongly associated with HLA-DRB1 risk alleles. This study aimed to explore the safety and biological and clinical effects of autologous DCs modified with a nuclear factor κB (NF-κB) inhibitor exposed to four citrullinated peptide antigens, designated "Rheumavax," in a single-center, open-labeled, first-in-human phase 1 trial. Rheumavax was administered once intradermally at two progressive dose levels to 18 human leukocyte antigen (HLA) risk genotype-positive RA patients with citrullinated peptide-specific autoimmunity. Sixteen RA patients served as controls. Rheumavax was well tolerated: adverse events were grade 1 (of 4) severity. At 1 month after treatment, we observed a reduction in effector T cells and an increased ratio of regulatory to effector T cells; a reduction in serum interleukin-15 (IL-15), IL-29, CX3CL1, and CXCL11; and reduced T cell IL-6 responses to vimentin(447-455)-Cit450 relative to controls. Rheumavax did not induce disease flares in patients recruited with minimal disease activity, and DAS28 decreased within 1 month in Rheumavax-treated patients with active disease. This exploratory study demonstrates safety and biological activity of a single intradermal injection of autologous modified DCs exposed to citrullinated peptides, and provides rationale for further studies to assess clinical efficacy and antigen-specific effects of autoantigen immunomodulatory therapy in RA.

Dendritic cell recruitment and activation in autoimmunity

“…These cells were intradermally administered every two week for two months and were able to increase the frequency of regulatory B cells in the peripheral blood of T1D patients without any side effects [247,248]. Furthermore, autologous DC ex-vivo generated in the presence of the tolerogenic agent BAY11-7082, a NF-kB inhibitor, were pulsed with a mixture of citrullinated peptides (called Rheumavax) and intradermally injected as single dose in RA patients that presented "shared epitope" related to increased risk to develop the disease and circulating levels of anti-citrullinated peptide antibodies (ACPA) [249]. In some patients, this treatment was able to increase the Treg/Teff ratio and decrease the circulating levels of proinflammatory cytokines [249].…”

“…Furthermore, autologous DC ex-vivo generated in the presence of the tolerogenic agent BAY11-7082, a NF-kB inhibitor, were pulsed with a mixture of citrullinated peptides (called Rheumavax) and intradermally injected as single dose in RA patients that presented "shared epitope" related to increased risk to develop the disease and circulating levels of anti-citrullinated peptide antibodies (ACPA) [249]. In some patients, this treatment was able to increase the Treg/Teff ratio and decrease the circulating levels of proinflammatory cytokines [249]. Another attempt has been performed in RA patients by using autologous DC generated in the presence of Dex and VitD3 and pulsed with synovial fluid (named AutoDECRA, ClinicalTrials.gov identifier NCT01352858) and then injected into the inflamed joints.…”

Pathogenetic insights from the treatment of rheumatoid arthritis

“…The principal feasibility of transfer of in vitro generated tolerogenic dendritic cells exposed to autologous antigens locally into the joints of RA patients has been shown recently [68,69]. Furthermore, a small trial showed that administration of allogeneic adipose-derived mesenchymal stem cells has an effect on treatment-resistant RA [70].…”

Smoking promotes exacerbated inflammatory features in dendritic cells of Chilean rheumatoid arthritis patients

“…Indeed, due to that functional phenotype of DCs represent a key point of decision to promote tolerance or inflammation in response to specific antigens, the use of tolerogenic DCs loaded with auto-antigens as therapy for the treatment of RA is currently under clinical trials 10,11 . Accumulating evidence suggests that RA develops in genetically predisposed individuals after exposure to environmental triggers.…”