Antigen-specific Immune Tolerance Research Articles

Autoantigenic Peptide and Immunomodulator Codelivery System for Rheumatoid Arthritis Treatment by Reestablishing Immune Tolerance.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by abnormal activation of CD4+ T cells and an imbalance of T helper 17 (Th17) and regulatory T (Treg) cells. Tolerogenic therapy via administration of self-antigens is a promising strategy for RA treatment, but delivery of autoantigens alone may exacerbate disease conditions. Current studies indicated that codelivery of autoantigens with immunomodulators can lead to a more tolerogenic immune response. Here, we constructed an autoantigen type II collagen peptide (CII250-270)- and immunomodulator leflunomide (LEF)-coloaded phosphatidylserine liposome vaccine (CII250-270-LEF-PSL) for RA treatment via induction of tolerant dendritic cells (tolDC) for further activation of Treg cells. The in vivo results showed that CII250-270-LEF-PSL can effectively induce tolDC, regulate the balance of Th1/Th2 and Th17/Treg, and reduce the secretion of pro-inflammatory cytokines (IFN-γ, IL-1β, and IL-17A) and IgG antibodies to inhibit synovial inflammation and bone erosion. Furthermore, our study also suggested that LEF regulated Th1 cell differentiation by inhibiting the activation of the JAK1/STAT1 signaling pathway, further alleviating RA. Overall, this work proved that the combination of autoantigenic peptides and immunomodulators was a promising modality for RA treatment by reestablishing antigen-specific immune tolerance, which also inspired additional insights into the development of combination therapies for the tolerability of RA.

Gut bacteria-derived serotonin promotes immune tolerance in early life.

The gut microbiota promotes immune system development in early life, but the interactions between the gut metabolome and immune cells in the neonatal gut remain largely undefined. Here, we demonstrate that the neonatal gut is uniquely enriched with neurotransmitters, including serotonin, and that specific gut bacteria directly produce serotonin while down-regulating monoamine oxidase A to limit serotonin breakdown. We found that serotonin directly signals to T cells to increase intracellular indole-3-acetaldehdye and inhibit mTOR activation, thereby promoting the differentiation of regulatory T cells, both ex vivo and in vivo in the neonatal intestine. Oral gavage of serotonin into neonatal mice resulted in long-term T cell-mediated antigen-specific immune tolerance toward both dietary antigens and commensal bacteria. Together, our study has uncovered an important role for specific gut bacteria to increase serotonin availability in the neonatal gut and identified a function of gut serotonin in shaping T cell response to dietary antigens and commensal bacteria to promote immune tolerance in early life.

Administration methods and dosage of poly(lactic acid)-glycol intervention to myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalitis mice

BackgroundMyelin oligodendrocyte glycoprotein-associated disorders (MOGAD) is an autoimmune central nervous system disease. Antigen-specific immune tolerance using nanoparticles such as Polylactic-co-glycolic acid (PLGA) have recently been used as a new therapeutic tolerization approach for CNS autoimmune diseases. We examined whether MOG1-125 conjugated with PLGA could induce MOG-specific immune tolerance in an experimental autoimmune encephalitis (EAE) mouse model. EAE was induced in sixty C57BL/6 J wild-type mice using MOG1-125 peptide with complete Freund’s Adjuvant. The mice were divided into 12 groups (n = 5 each) to test the ability of MOG1-125 conjugated PLGA intervention to mitigate the severity or improve the outcomes from EAE with and without rapamycin compared to antigen alone or PLGA alone. EAE score and serum MOG-IgG titers were compared among the interventions.Kindly check and confirm the processed Affiliation “4” is appropriate.I confirmed the Aff 4.Affiliation: Corresponding author information have been changed to present affiliation. Kindly check and confirm.I checked and confirmed the Corresponding author's information.ResultsMice with EAE that were injected intraperitoneally with MOG1-125 conjugated PLGA + rapamycin complex showed dose-dependent mitigation of EAE score. Intraperitoneal and intravenous administration resulted in similar clinical outcomes, whereas 80% of mice treated with subcutaneous injection had a recurrence of clinical score worsening after approximately 1 week. Although there was no significant difference in EAE scores between unconjugated-PLGA and MOG-conjugated PLGA, serum MOG-IgG tended to decrease in the MOG-conjugated PLGA group compared to controls.ConclusionIntraperitoneal administration of PLGA resulted in dose-dependent and longer-lasting immune tolerance than subcutaneous administration. The induction of immune tolerance using PLGA may represent a future therapeutic option for patients with MOGAD.

Transdermally delivered tolerogenic nanoparticles induced effective immune tolerance for asthma treatment

Induction of antigen-specific immune tolerance for the treatment of allergic or autoimmune diseases is an attractive strategy. Herein, we investigated the protective effect of a transdermal microneedle patch against allergic asthma by stimulating allergen-specific immune tolerance. We fabricated biodegradable tolerogenic nanoparticles (tNPs) that are loaded with a model allergen ovalbumin (OVA) and an immunomodulator rapamycin, and filled the tNPs into microneedle tips by centrifugation to form sustained-release microneedles. After intradermal immunization, the microneedles successfully delivered the cargos into the skin and sustainedly released them for over 96 h. Importantly, the microneedles induced allergen-specific regulatory T cells (Treg), decreased the levels of pro-inflammatory cytokines and antibodies while increased anti-inflammation cytokines, finally leading to restored immune homeostasis. The lung tissue analysis illustrated that the sustained-release microneedles significantly reduced the infiltration of eosinophils, decreased the accumulation of mucus and collagen, and significantly relived asthma symptoms. Our results suggested that the sustained-release microneedle-based transdermal delivery system can induce antigen-specific immune tolerance with improved compliance and efficacy, providing a new therapeutic strategy for the treatment of allergic and autoimmune diseases.

Immune tolerance promotion by LSEC-specific lentiviral vector-mediated expression of the transgene regulated by the stabilin-2 promoter

Liver sinusoidal endothelial cells (LSECs) are specialized endocytic cells that clear the body from blood-borne pathogens and waste macromolecules through scavenger receptors (SRs). Among the various SRs expressed by LSECs is stabilin-2 (STAB2), a class H SR that binds to several ligands, among which endogenous coagulation products. Given the well-established tolerogenic function of LSECs, we asked whether the STAB2 promoter (STAB2p) would enable us to achieve LSEC-specific lentiviral vector (LV)-mediated transgene expression, and whether the expression of this transgene would be maintained over the long-term due to tolerance induction. Here we show that STAB2p ensures LSEC-specific green fluorescent protein (GFP) expression by LV in the absence of a specific cytotoxic CD8+ T cell immune response, even in the presence of GFP-specific CD8+ T cells, confirming the robust tolerogenic function of LSECs. Finally, we show that our delivery system can partially and permanently restore FVIII activity in a mouse model of severe hemophilia A without the formation of anti-FVIII antibodies. Overall, our findings establish the suitability of STAB2p for long-term LSEC-restricted expression of therapeutic proteins, such as FVIII, or to achieve antigen-specific immune tolerance in auto-immune diseases.

ROS-Scavenging Lignin-Based Tolerogenic Nanoparticle Vaccine for Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a demyelinating autoimmune disease, in which the immune system attacks myelin. Although systemic immunosuppressive agents have been used to treat MS, long-term treatment with these drugs causes undesirable side effects such as altered glucose metabolism, insomnia, and hypertension. Herein, we propose a tolerogenic therapeutic vaccine to treat MS based on lignin nanoparticles (LNP) with intrinsic reactive oxygen species (ROS)-scavenging capacity derived from their phenolic moieties. The LNP loaded with autoantigens of MS allowed for inducing tolerogenic DCs with low-level expression of costimulatory molecules while presenting antigenic peptides. Intravenous injection of an LNP-based tolerogenic vaccine into an experimental autoimmune encephalomyelitis (EAE) model led to durable antigen-specific immune tolerance via inducing regulatory T cells (Tregs). Autoreactive T helper type 1 cells, T helper type 17 cells, and inflammatory antigen presentation cells (APCs) were suppressed in the central nervous system (CNS), ameliorating ongoing MS in early and late disease states. Additionally, the incorporation of dexamethasone into an LNP-based tolerogenic nanovaccine could further improve the recovery of EAE mice in the severe chronic stage. As lignin is the most abundant biomass and waste byproduct in the pulping industry, a lignin-based tolerogenic vaccine could be a novel, cost-effective, high-value vaccine platform with potent therapeutic efficiency in treating autoimmune diseases.

Rapamycin nanoparticles increase the therapeutic window of engineered interleukin-2 and drive expansion of antigen-specific regulatory T cells for protection against autoimmune disease

Interleukin-2 (IL-2) therapies targeting the high affinity IL-2 receptor expressed on regulatory T cells (Tregs) have shown promising therapeutic benefit in autoimmune diseases through nonselective expansion of pre-existing Treg populations, but are potentially limited by the inability to induce antigen-specific Tregs, as well as by dose-limiting activation of effector immune cells in settings of inflammation. We recently developed biodegradable nanoparticles encapsulating rapamycin, called ImmTOR, which induce selective immune tolerance to co-administered antigens but do not increase total Treg numbers. Here we demonstrate that the combination of ImmTOR and an engineered Treg-selective IL-2 variant (termed IL-2 mutein) increases the number and durability of total Tregs, as well as inducing a profound synergistic increase in antigen-specific Tregs when combined with a target antigen. We demonstrate that the combination of ImmTOR and an IL-2 mutein leads to durable inhibition of antibody responses to co-administered AAV gene therapy capsid, even at sub-optimal doses of ImmTOR, and provides protection in autoimmune models of type 1 diabetes and primary biliary cholangitis. Importantly, ImmTOR also increases the therapeutic window of engineered IL-2 molecules by mitigating effector immune cell expansion and preventing exacerbation of disease in a model of graft-versus-host-disease. At the same time, IL-2 mutein shows potential for dose-sparing of ImmTOR. Overall, these results establish that the combination of ImmTOR and an IL-2 mutein show synergistic benefit on both safety and efficacy to provide durable antigen-specific immune tolerance to mitigate drug immunogenicity and to treat autoimmune diseases.

Regulatory T cells in autoimmune kidney diseases and transplantation.

Regulatory T (Treg) cells that express the transcription factor forkhead box protein P3 (FOXP3) are naturally present in the immune system and have roles in the maintenance of immunological self-tolerance and immune system and tissue homeostasis. Treg cells suppress T cell activation, expansion and effector functions by various mechanisms, particularly by controlling the functions of antigen-presenting cells. They can also contribute to tissue repair by suppressing inflammation and facilitating tissue regeneration, for example, via the production of growth factors and the promotion of stem cell differentiation and proliferation. Monogenic anomalies of Treg cells and genetic variations of Treg cell functional molecules can cause or predispose patients to the development of autoimmune diseases and other inflammatory disorders, including kidney diseases. Treg cells can potentially be utilized or targeted to treat immunological diseases and establish transplantation tolerance, for example, by expanding natural Treg cells in vivo using IL-2 or small molecules or by expanding them in vitro for adoptive Treg cell therapy. Efforts are also being made to convert antigen-specific conventional T cells into Treg cells and to generate chimeric antigen receptorTreg cells from natural Treg cells for adoptive Treg cell therapies with the aim of achieving antigen-specific immune suppression and tolerance in the clinic.

Immunosuppressive Polymeric Nanoparticles Targeting Dendritic Cells Alleviate Lupus Disease in Fcgr2b-/- Mice by Mediating Antigen-Specific Immune Tolerance.

Dendritic cells (DCs) are the most potent antigen-presenting cells that have multifaceted functions in the control of immune activation and tolerance. Hyperresponsiveness and altered tolerogenicity of DCs contribute to the development and pathogenesis of system lupus erythematosus (SLE); therefore, DC-targeted therapies aimed at inducing specific immune tolerance have become of great importance for the treatment of SLE. This study developed a new nanoparticle (NP) containing a biodegradable PDMAEMA-PLGA copolymer for target-oriented delivery to DCs in situ. PDMAEMA-PLGA NPs provided sustained drug release and exhibited immunosuppressive activity in FLT3L and GM-CSF-derived bone marrow in conventional DCs (BM-cDCs). PDMAEMA-PLGA NPs improved dexamethasone capability to convert wild-type and Fcgr2b-/- BM-cDCs from an immunogenic to tolerogenic state, and BM-cDCs treated with dexamethasone-incorporated PDMAEMA-PLGA NPs (Dex-NPs) efficiently mediated regulatory T cell (Treg) expansion in vitro. Dex-NP therapy potentially alleviated lupus disease in Fcgr2b-/- mice by mediating Foxp3+ Treg expansion in an antigen-specific manner. Our findings substantiate the superior efficacy of DC-targeted therapy using the PDMAEMA-PLGA NP delivery system and provide further support for clinical development as a potential therapy for SLE. Furthermore, PDMAEMA-PLGA NP may be a versatile platform for DC-targeted therapy to induce antigen-specific immune tolerance to unwanted immune responses that occur in autoimmune disease, allergy, and transplant rejection.

Competitive ELISA for the identification of 35-55 myelin oligodendrocyte glycoprotein immunodominant epitope conjugated with mannan.

Analogs of immunodominant myelin peptides involved in multiple sclerosis (MS: the most common autoimmune disease) have been extensively used to modify the immune response over the progression of the disease. The immunodominant 35-55 epitope of myelin oligodendrocyte glycoprotein (MOG35-55 ) is an autoantigen appearing in MS and stimulates the encephalitogenic T cells, whereas mannan polysaccharide (Saccharomyces cerevisiae) is a carrier toward the mannose receptor of dendritic cells and macrophages. The conjugate of mannan-MOG35-55 has been extensively studied for the inhibition of chronic experimental autoimmune encephalomyelitis (EAE: an animal model of MS) by inducing antigen-specific immune tolerance against the clinical symptoms of EAE in mice. Moreover, it presents a promising approach for the immunotherapy of MS under clinical investigation. In this study, a competitive enzyme-linked immunosorbent assay (ELISA) was developed to detect the MOG35-55 peptide that is conjugated to mannan. Intra- and inter-day assay experiments proved that the proposed ELISA methodology is accurate and reliable and could be used in the following applications: (i) to identify the peptide (antigen) while it is conjugated to mannan and (ii) to adequately address the alterations that the MOG35-55 peptide may undergo when it is bound to mannan during production and stability studies.

Oral delivery of bi-autoantigens by bacterium-like particles (BLPs) against autoimmune diabetes in NOD mice

Induction of oral tolerance by vaccination with type 1 diabetes mellitus (T1DM)-associated autoantigens exhibits great potential in preventing and treating this autoimmune disease. However, antigen degradation in the gastrointestinal tract (GIT) limits the delivery efficiency of oral antigens. Previously, bacterium-like particles (BLPs) have been used to deliver a single-chain insulin (SCI-59) analog (BLPs-SCI-59) or the intracellular domain of insulinoma-associated protein 2 (IA-2ic) (BLPs-IA-2ic). Both monovalent BLPs vaccines can suppress T1DM in NOD mice by stimulating the corresponding antigen-specific oral tolerance, respectively. Here, we constructed two bivalent BLPs vaccines which simultaneously deliver SCI-59 and IA-2ic (Bivalent vaccine-mix or Bivalent vaccine-SA), and evaluated whether there is an additive beneficial effect on tolerance induction and suppression of T1DM by treatment with BLPs-delivered bi-autoantigens. Compared to the monovalent BLPs vaccines, oral administration of the Bivalent vaccine-mix could significantly reduce morbidity and mortality in T1DM. Treatment with the bivalent BLPs vaccines (especially Bivalent vaccine-mix) endowed the mice with a stronger ability to regulate blood glucose and protect the integrity and function of pancreatic islets than the monovalent BLPs vaccines treatment. This additive effect of BLPs-delivered bi-autoantigens on T1DM prevention may be related to that SCI-59- and IA-2-specific Th2-like immune responses could be induced, which was more beneficial for the correction of Th1/Th2 imbalance. In addition, more CD4+CD25+Foxp3+ regulatory T cells (Tregs) were induced by treatment with the bivalent BLPs vaccines than did the monovalent BLPs vaccines. Therefore, multiple autoantigens delivered by BLPs maybe a promising strategy to prevent T1DM by efficiently inducing antigen-specific immune tolerance.

Treg-based immunotherapy for antigen-specific immune suppression and stable tolerance induction: a perspective.

FoxP3-expressing regulatory T cells (Tregs), whether naturally generated in the immune system or unnaturally induced from conventional T cells (Tconvs) in the laboratory, have much therapeutic value in treating immunological diseases and establishing transplantation tolerance. Natural Tregs (nTregs) can be selectively expanded in vivo by administration of low-dose IL-2 or IL-2 muteins for immune suppression. For adoptive Treg cell therapy, nTregs can be expanded in vitro by strong antigenic stimulation in the presence of IL-2. Synthetic receptors such as CAR can be expressed in nTregs to equip them with a particular target specificity for suppression. In addition, antigen-specific Tconvs can be converted in vitro to functionally stable Treg-like cells by a combination of antigenic stimulation, FoxP3 induction, and establishment of the Treg-type epigenome. This review discusses current and prospective strategies for Treg-based immune suppression and the issues to be resolved for achieving stable antigen-specific immune suppression and tolerance induction in the clinic by targeting Tregs.

Particle-Based therapies for antigen specific treatment of type 1 diabetes

Type 1 diabetes mellitus (T1D) is the leading metabolic disorder in children worldwide. Over time, incidence rates have continued to rise with 20 million individuals affected globally by the autoimmune disease. The current standard of care is costly and time-consuming requiring daily injections of exogenous insulin. T1D is mediated by autoimmune effector responses targeting autoantigens expressed on pancreatic islet β-cells. One approach to treat T1D is to skew the immune system away from an effector response by taking an antigen-specific approach to heighten a regulatory response through a therapeutic vaccine. An antigen-specific approach has been shown with soluble agents, but the effects have been limited. Micro or nanoparticles have been used to deliver a variety of therapeutic agents including peptides and immunomodulatory therapies to immune cells. Particle-based systems can be used to deliver cargo into the cell and microparticles can passively target phagocytic cells. Further, surface modification and controlled release of encapsulated cargo can enhance delivery over soluble agents. The induction of antigen-specific immune tolerance is imperative for the treatment of autoimmune diseases such as T1D. This review highlights studies that utilize particle-based platforms for the treatment of T1D.

Tissue-Targeted Drug Delivery Strategies to Promote Antigen-Specific Immune Tolerance.

During autoimmunity or organ transplant rejection, the immune system attacks host or transplanted tissue, causing debilitating inflammation for millions of patients. There is no cure for most of these diseases. Further, available therapies modulate inflammation through nonspecific pathways, reducing symptoms but also compromising patients' ability to mount healthy immune responses. Recent preclinical advances to regulate immune dysfunction with vaccine-like antigen specificity reveal exciting opportunities to address the root cause of autoimmune diseases and transplant rejection. Several of these therapies are currently undergoing clinical trials, underscoring the promise of antigen-specific tolerance. Achieving antigen-specific tolerance requires precision and often combinatorial delivery of antigen, cytokines, small molecule drugs, and other immunomodulators. This can be facilitated by biomaterial technologies, which can be engineered to orient and display immunological cues, protect against degradation, and selectively deliver signals to specific tissues or cell populations. In this review, some key immune cell populations involved in autoimmunity and healthy immune tolerance are described. Opportunities for drug delivery to immunological organs are discussed, where specialized tissue-resident immune cells can be programmed to respond in unique ways toward antigens. Finally, cell- and biomaterial-based therapies to induce antigen-specific immune tolerance that are currently undergoing clinical trials are highlighted.

Immunomodulatory nano-preparations for rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease (AD) caused by the aberrant attack of the immune system on its own joint tissues. Genetic and environmental factors are the main reasons of immune system impairment and high incidence of RA. Although there are medications on the market that lessen disease activity, there is no known cure for RA, and patients are at risk in varying degrees of systemic immunosuppression. By transporting (encapsulating or surface binding) RA-related self-antigens, nucleic acids, immunomodulators, or cytokines, tolerogenic nanoparticles—also known as immunomodulatory nano-preparations—have the potential to gently regulate local immune responses and ultimately induce antigen-specific immune tolerance. We review the recent advances in immunomodulatory nano-preparations for delivering self-antigen or self-antigen plus immunomodulator, simulating apoptotic cell avatars in vivo, acting as artificial antigen-presenting cells, and based on scaffolds and gels, to provide a reference for developing new immunotherapies for RA.

Immunosuppressive biomaterial-based therapeutic vaccine to treat multiple sclerosis via re-establishing immune tolerance

Current therapies for autoimmune diseases, such as multiple sclerosis (MS), induce broad suppression of the immune system, potentially promoting opportunistic infections. Here, we report an immunosuppressive biomaterial-based therapeutic vaccine carrying self-antigen and tolerance-inducing inorganic nanoparticles to treat experimental autoimmune encephalomyelitis (EAE), a mouse model mimicking human MS. Immunization with self-antigen-loaded mesoporous nanoparticles generates Foxp3+ regulatory T-cells in spleen and systemic immune tolerance in EAE mice, reducing central nervous system-infiltrating antigen-presenting cells (APCs) and autoreactive CD4+ T-cells. Introducing reactive oxygen species (ROS)-scavenging cerium oxide nanoparticles (CeNP) to self-antigen-loaded nanovaccine additionally suppresses activation of APCs and enhances antigen-specific immune tolerance, inducing recovery in mice from complete paralysis at the late, chronic stage of EAE, which shows similarity to chronic human MS. This study clearly shows that the ROS-scavenging capability of catalytic inorganic nanoparticles could be utilized to enhance tolerogenic features in APCs, leading to antigen-specific immune tolerance, which could be exploited in treating MS.

Phase 1b Trial of Anti-Immunoglobulin-like Transcript 3 Monoclonal Antibody MK-0482 Monotherapy in Relapsed/Refractory Acute Myeloid Leukemia and Chronic Myelomonocytic Leukemia

Background: Immunoglobulin-like transcript 3 (ILT3) is a cell surface inhibitory receptor expressed on various immune cells including dendritic cells, monocytic myeloid cells, and macrophages. The expression of ILT3 on dendritic cells and myeloid cells is thought to be involved in immune suppression and antigen-specific immune tolerance, contributing to an immunosuppressive tumor microenvironment. Acute myeloid leukemia (AML) is a type of cancer characterized by bone marrow that makes a large number of abnormal blood cells. In monocytic AML, ILT3 is highly expressed, and its signaling can mediate T-cell suppression and promote tumor infiltration (Deng M et al. Nature. 2018;562:605-609). Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by dysplasia, abnormal production and accumulation of monocytic cells, and with an elevated risk of transforming into AML. Based on the M2GEN database, ILT3 is also highly expressed in CMML. Thus, targeting ILT3 may exhibit antitumor activity in patients with AML and CMML. Currently, limited effective treatments are available for AML and CMML, especially in the relapse and refractory setting. MK-0482, a humanized IgG4 anti-ILT3 monoclonal antibody, has been evaluated as monotherapy and in combination with pembrolizumab at doses ≤2250 mg every 3 weeks (Q3W) in patients with advanced solid tumors. Patients treated with MK-0482 had a manageable safety profile, and modest antitumor activity was observed with MK-0482 plus pembrolizumab (Gutierrez M et al. J Clin Oncol. 2022;40. Abstract 2505). In this phase 1b study (NCT05038800), we are evaluating the safety and the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of MK-0482 in relapsed or refractory (r/r) AML and CMML. Study Design and Methods: Adult patients with AML with myelomonocytic or monoblastic/monocytic differentiation or CMML and with confirmed refractory or relapsed disease after treatment with available therapies will be eligible for enrollment. All patients must have an ECOG performance status of 0-2, adequate organ function, and a white blood cell count ≤20 × 109/L. Patients with active central nervous system leukemia, isolated extramedullary disease (ie no leukemic involvement), acute promyelocytic leukemia, or who have previously received allogeneic stem cell or organ transplant <60 days of treatment will be excluded. In part 1 (dose escalation), MK-0482 will be evaluated at dose levels ranging from 7.5 mg to 750 mg Q3W for ≤35 cycles with an accelerated titration design followed by a modified toxicity probability interval design in ~20 patients. After the recommended phase 2 dose (RP2D) is determined, 10 to 15 additional patients with AML with myelomonocytic or monoblastic/monocytic differentiation will be enrolled in part 2 (dose expansion). The primary objective of the study is to determine safety and tolerability and RP2D. Secondary objectives include characterizing the PK profile of MK-0482 monotherapy and antileukemia activities in AML as assessed by complete remission (CR), composite CR, and objective response per the 2017 European Leukemia Net AML response criteria. Exploratory objectives include assessment of receptor occupancy in peripheral blood and tumor biopsies, molecular biomarkers, and antileukemic activities in patients with CMML. Dose-limiting toxicities will be observed for 21 days after the first dose in cycle 1 and adverse events (AEs) will be assessed through 30 days after treatment discontinuation (90 days for serious AEs; 30 days if new anticancer therapy is initiated) per National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Disease assessment will be performed by investigator at baseline and prior to day 1 of cycles 3, 5, and 7, followed by every 3 cycles until disease progression or confirmed CR. Samples for PK analyses will be collected before and after treatment on day 1 of cycles 1-4, 6, 8, and every 4 cycles thereafter. The study is currently ongoing.

From vaccines to nanovaccines: A promising strategy to revolutionize rheumatoid arthritis treatment.

Rheumatoid arthritis (RA) is a joint-related autoimmune disease that is difficult to cure. Most therapeutics act to alleviate the symptoms but not correct the causes of RA. Novel strategies that specifically target the causes are highly needed for RA management. Currently, early interruption of RA is increasingly suggested but the corresponding therapeutics are not available. Vaccines that have shown great success to combat infection, cancer, degenerative diseases, autoimmune diseases, etc. are ideal candidates for a new generation of anti-RA therapeutics to correct the causes and prevent RA or interrupt RA in early phases. Anti-RA vaccines can be divided into two major categories. One is to induce neutralizing antibodies and the other is to induce antigen-specific immune tolerance. The vaccines are inherently linked to nanotechnology because they usually need a biomacromolecule or carrier to provoke sufficient immune responses. In the past decade, designed nanocarriers such as nanoparticles, liposomes, nanoemulsion, etc., have been applied to optimize the vaccines for autoimmune disease treatment. Nanotechnology endows vaccines with a higher biostability, tunable in vivo behavior, better targeting, co-delivery with stimulatory agents, regulatory effects on immune responses, etc. In this review, unmet medical needs for RA treatment and anti-RA vaccinology are first introduced. The development of anti-RA therapies from vaccines to nanovaccines are then reviewed and perspectives on how nanotechnology promotes vaccine development and advancement are finally provided. In addition, challenges for anti-RA vaccine development are summarized and advantages of nanovaccines are analyzed. In conclusion, nanovaccines will be a promising strategy to revolutionize the treatment of RA by correcting the causes in an early phase of RA.

Symposium 2-2 - Challenges in elucidating the mechanisms of fetal recognition and tolerance by T cells

The fetus is a semi-graft expressing paternally derived antigens that are foreign to the mother, however, it is not rejected by the mother because of the establishment of feto-maternal tolerance. Maternal cytotoxic T cells (CTLs) and CD4+ T helper cells (CD4+Tconv) recognize fetal antigens at the T cell receptor (TCR), while regulatory T cells (Treg) suppress immune responses. To investigate the role of antigen-specific Tregs and CTLs in human pregnancy, we analyzed the TCR variations from single T cells from decidua. In normal pregnancies, the number of Tregs with specific TCRs which were presumed to be paternal antigen-specific Tregs increased in a biased manner. In preeclampsia, antigen specific Tregs were decreased. This suggests that induction of antigen-specific immune tolerance by Tregs was inadequate in preeclampsia. Next, to comprehensively search for pathologically relevant molecules in Tregs and CD4+Tconv that could be targets for immunological therapy, we performed single-cell transcriptome analysis of T cells. The results suggest that Th17 among CD4+Tconvs is increased in PE, but the differentiation pathway may be different from that of Tregs. We would like to mention the results of this study and the prospects for immunological approaches to PE therapy.

Drug design for induction of antigen-specific immune tolerance

Drug design for induction of antigen-specific immune tolerance