NK cell subsets and their role in allergy

INTRODUCTION: NK cells represent a distinct lymphocyte population with extensive cytolytic activity and a variety of other functions, including regulation of hemopoiesis, suppressor functions and immunoglobulin production. Recently, reports suggest that NK cells also display potent regulatory functions via secretion of cytokines or cell-contact-dependent mechanisms. Thus NK cells may regulate innate and adaptive immune responses and play a role in immune homeostasis. AREAS COVERED: NK cells play important roles in viral infections, autoimmunity, pregnancy, cancer and bone marrow transplantation. Although the role of NK cells in allergic diseases is poorly described, recent findings suggest their role in allergy. EXPERT OPINION: Recent developments in the study of NK cell subsets have support their role in allergic diseases that contribute to allergen-specific immune suppression, allergen-specific T(H)1 cell generation as well as IgE and other Ig production.     

Designing multivalent proteins based on natural killer cell receptors and their ligands as immunotherapy for cancer

ABSTRACT

Introduction: Natural killer (NK) cells are an important component of the innate immune system that play a key role in host immunity against cancer. NK cell recognition and activation is based on cell surface receptors recognizing specific ligands that are expressed on many types of tumor cells. Some of these receptors are capable of activating NK cell function while other receptors inhibit NK cell function. Therapeutic approaches to treat cancer have been developed based on preventing NK cell inhibition or using NK cell receptors and their ligands to activate NK cells or T cells to destroy tumor cells.

Areas covered: This article describes the various strategies for targeting NK cell receptors and NK cell receptor ligands using multivalent proteins to activate immunity against cancer.

Expert opinion: NK cell receptors work in synergy to activate NK cell effector responses. Effective anti-cancer strategies will need to not only kill tumor cells but must also lead to the destruction of the tumor microenvironment. Immunotherapy based on NK cells and their receptors has the capacity to accomplish this through triggering lymphocyte cytotoxicity and cytokine production.     

The rise of human stem cell-derived natural killer cells for cancer immunotherapy

Introduction: Natural killer (NK) cell therapy has been proven to be safe and clinically effective for the treatment of multiple cancers, in particular blood cancers. Most of the clinical trials use primary NK cells from peripheral blood or umbilical cord blood, or NK-92 cells. Each cell source is confined by limitations, such as donor dependence, low persistence in vivo, and its difficulty to genetically modify. Thus, there is an urgent need to explore novel NK cell sources for clinical use.

Areas covered: This article highlights the recent progress in utilizing stem cell-derived NK cells as anticancer therapies and strategies to improve their antitumor activities.

Expert commentary: Stem cell-derived NK cells are homogenous, easy to genetically modify on a clonal level, and can be expanded to clinical scale. They may therefore arise as an ideal population for developing off-the-shelf, standardized adoptive NK cell therapeutic products.     

T cell tolerance to inhaled allergens: mechanisms and therapeutic approaches

Background: Specific immune response to allergens is decisive in the development of clinically healthy or allergic states. Objective: Recent developments in the mechanisms of allergen-specific peripheral tolerance can be used for future treatment modalities. Methods: This review focuses on recent developments in allergen tolerance. Results/conclusion: The balance between allergen-specific IL-10-secreting T regulatory cells (Tr1) and T helper 2 (Th2) cells appears to be decisive in the development of allergic and healthy immune response against allergens. Induction of IL-10- and TGF-β-producing Tr1 cells, IgG4-isotype-blocking antibodies, and suppressed mast cells, basophils and eosinophils represent major components of a relatively normalized immune response after allergen-specific immunotherapy and healthy immune response to aeroallergens in sensitized individuals.     

CCL5 as an adjuvant for cancer immunotherapy

Importance of the field: To date cancer immunotherapy has only achieved limited clinical efficacy, thus more efficient immunotherapeutic approaches need to be explored. The CC chemokine CCL5 plays a role in chemoattraction and activation of immune cells implying its potential clinical application as an adjuvant for boosting anti-tumor immunity, although an effect on carcinogenesis and tumor cell invasiveness is also reported to be associated with CCL5.

Areas covered in this review: Recent progress in exploiting CCL5 as an adjuvant for cancer prevention and treatment, and updated understanding on how CCL5 is involved in tumor invasiveness and carcinogenesis.

What the reader will gain: CCL5 represents a natural adjuvant for enhancing anti-tumor immune responses. However, animal experiments and clinical reports suggest that CCL5 plays a role in carcinogenesis and invasiveness of tumor cells. Therefore, a CCL5-based cancer therapeutic approach needs to avoid the CCL5-associated potential detrimental effects.

Take home message: CCL5 has a pre-eminent role in chemotaxis and activation of a wide spectrum of immune cells. CCL5 functions as an adjuvant to boost anti-tumor immunity by diverse protocols such as co-immunization of recombinant CCL5 protein with tumor-associated antigen, vaccination with CCL-5-expressing tumor cells, or viral vector delivery of CCL5 cDNA into growing tumor. CCL5 may also promote tumor cell survival, proliferation and invasion by different mechanisms.     

Prevalence of positive IGRAs and innate immune system in HIV-infected individuals in Japan

IntroductionHuman immunodeficiency virus (HIV) infected individuals are at increased risk of developing active tuberculosis (TB). TB incidence remains higher than in non-HIV subjects after antiretroviral therapy (ART) initiation. This study was conducted to estimate the prevalence of positive IGRA, reflecting latent tuberculosis infection and/or a history of active TB, in HIV-infected individuals after ART initiation in Japan.MethodsTwo IGRAs (Interferon (IFN)-γ release assays), QuantiFERON®-TB Gold Plus (QFT-Plus) and T-Spot®.TB (TSPOT), were used. We also analyzed the TB associated risk factors for the IGRAs results and the role of CD4⁺ T-cells, CD8⁺ T-cells and NK cells for producing IFN-γ. We also analyzed the risk factors for positive IGRA responses and the role of CD4⁺ T-cells, CD8⁺ T-cells and NK cells for producing IFN-γ.ResultsOne hundred eight-four subjects were prospectively enrolled. Median age was 49 years. The positivity rates of QFT-Plus and TSPOT were 7.6% [95%CI 4.6–12.4] and 2.7% [95%CI 1.2–6.2], respectively, with significant difference. TB-associated risk factors and NK cells ≥300/μL were selected as independently significant factors by multivariate logistic regression. The NK cell count revealed significant linear regression with IFN-γ production responding to TB-specific antigens.ConclusionsThe prevalence of positive IGRAs was 2.7%–7.6%. QFT-Plus would be practical for a higher positivity rate and reflect TB risk factors. The innate immune system, referring to IFN-γ production, plays an important role in the immune response to TB-specific antigens even after initiating ART.     

Allogenic bone-marrow-derived mesenchymal stem cells transplantation as a novel therapy for systemic lupus erythematosus

Importance of the field: Bone-marrow-derived mesenchymal stem cells (BMMSC) are multipotent non-hematopoietic progenitor cells that are being explored as a promising new treatment for tissue regeneration. Although their immunomodulatory properties are not yet completely understood, their low immunogenic potential together with their effects on immune response make them a promising therapeutic tool for severe refractory autoimmune diseases including systemic lupus erythematosus (SLE).

Area covered in this review: Our aim is to discuss recent progress in understanding the role of malfunctioning BMMSC in etiopathogenesis of SLE and to explore allogenic BMMSC transplantation as a potential therapy for SLE.

What the reader will gain: Recent evidence suggests that the functions of BMMSC are disrupted in SLE pathology. This malfunction may result as a corollary of the disease, or may play a more fundamental role in its etiopathogenesis. We provide a brief characterization of BMMSC immunomodulatory effects, and describe our current understanding of the mechanisms by which it plays a part in treating SLE. We also present our clinical trial using allogenic BMMSC in this context.

Take home message: Allogenic BMMSC appear to be a safe therapeutic option for treatment-resistant SLE as illustrated in our clinical trial.     

Hyper-interleukin-11 novel designer molecular adjuvant targeting gp130 for whole cell cancer vaccines

Background: Hyper-IL-11 (H11) is a fusion protein comprising IL-11 and soluble IL-11 receptor directly targeting gp130. We evaluated efficacy of H11 as a molecular adjuvant in therapeutic whole tumor cell vaccine formulation.

Methods: H11 was tested in ectopic and orthotopic murine renal cell carcinoma (RENCA) models. H11 cDNA was transduced into RENCA cells (RENCA-H11). Mice were immunized with RENCA-H11 or control vaccine (RENCA-IRR) in prophylactic, adjuvant and therapeutic settings. Tumor formation, survival and immune mechanisms activated by H11 were studied.

Results: Biologically active H11 was secreted by RENCA-H11 cells. Immunization with RENCA-H11 resulted in mounting specific anti-RENCA response. Treatment of tumor bearing mice in adjuvant setting prevented disease recurrence in therapeutic setting eradicated tumors. In induction phase H11 inhibited T-regulatory cell formation and activated recruitment and maturation of dendritic cells. Downstream of immunization tumors were densely infiltrated by CD8⁺, CD4⁺, NK cells, cells expressing CD8⁺CD69⁺ and CD4⁺CD62L^low.

Conclusions: H11 is a good candidate for adjuvant of whole tumor cell vaccines. Direct targeting of gp130 leads to induction of specific and long lasting anticancer immune response. Enhancement of tumor antigen presentation, abrogation of immune tolerance, and activation of NK cells and generation of memory cells lead to eradication of existing tumors.     

Allogeneic stem cell transplantation in multiple myeloma: immunotherapy and new drugs

Introduction: Autologous (auto) stem cell transplantation (SCT) and the development of new drugs have improved the survival of multiple myeloma (MM) patients. By contrast, though potentially curative, the use of allogeneic (allo)-SCT is controversial.

Areas covered: A review has been conducted to examine the current evidence for the use of allo-SCT in MM. We have examined novel cell therapies that may be exploited to induce myeloma-specific immune responses including the new promising frontier of chimeric antigen receptor (CAR)-T and -natural killer (NK) cells.

Expert opinion: One of the major controversies facing researchers in exploring the allo approach is the remarkable recent treatment improvement observed with second- and third-generation proteasome inhibitors and immunomodulatory drugs, monoclonal antibodies and deacetylase inhibitors. Despite these great advances, the disease remains to be incurable and allo-SCT may still play a role in the cure of MM. We think that allo-SCT conserves a role in MM and its curative potential in high-risk patients should be explored in the setting of control clinical trials. Novel cell therapies such as CAR technologies may open new avenues of research toward a potential cure. Data from currently ongoing prospective studies will be helpful to clarify pending clinical questions.     

Regulatory T cells in HBV and HCV liver diseases: implication of regulatory T lymphocytes in the control of immune response

Importance of the field: Hepatic cirrhosis is a frequent consequence of chronic hepatitis infection (HBV and HCV) or alcohol abuse and the most common cause of hepatocellular carcinoma (HCC). Currently, liver transplantation remains the only effective therapeutic approach for cirrhosis-related HCC patients. The evolution of the pathology strongly depends on immunological mechanisms.

Areas covered in this review: Despite the presence of specific T cells, viral chronic infection and continuous tumor growth suggest a failure of immune control. It appears that direct suppression of antiviral or antitumor effector cells by regulatory T cells plays a pivotal role in the impairment of immune response. Several types of regulatory T cells have been described, natural regulatory T cells (nTreg) and induced-type 1 regulatory T cells (Tr1) being the best characterized.

What the reader will gain: Currently, there is no evidence for a direct implication of regulatory T cells in the evolution of hepatitis, especially concerning chronic infection, cirrhosis late stage and HCC progress. However, recent studies show that regulatory T cells are implicated in the modulation of HBV- and HCV-associated immune response, thus, promoting HCC progress.

Take home message: Therefore, nTreg and Tr1 cells seem to play an important role in the control of immune response leading to chronic hepatitis infection and progression of the pathology to cirrhosis and HCC.     

AllergoOncology: Role of immune cells and immune proteins

BackgroundImmune cells and immune proteins play a pivotal role in host responses to pathogens, allergens and cancer. Understanding the crosstalk between allergic response and cancer, immune surveillance, immunomodulation, role of immunoglobulin E (IgE)‐mediated functions and help to develop novel therapeutic strategies. Allergy and oncology show two opposite scenarios: whereas immune tolerance is desired in allergy, it is detrimental in cancer.AimThe current review provides an update on the role of immune cells and immune proteins in allergy and cancer fields.MethodsAuthors investigated the role of relevant immunological markers and the correlation with cancer progression or cancer suppression.ResultsActivated immune cells such as macrophages ‘M1’, dendritic cells (DCs), innate lymphoid cells (ILC2), NK cells, Th1, follicular T helper cells (TFH), TCD8+, B lymphocytes and eosinophils have inhibitory effects on tumourigenesis, while tolerogenic cells such as macrophages ‘M2,’ tolerogenic DCs, ILC3, T and B regulatory lymphocytes appear to favour carcinogenesis. Mastocytes and alarmins can have both effects. RIgE antibodies and CCCL5 chemokine have an anticancer role, whereas IgG4, free light chains, Il‐10, TGF‐β, lipocalin‐2, CCL1 chemokine promote cancer progression. Fundamental is also the contribution of epigenetic changes regulated by the microRNA in cancer progression.ConclusionThis knowledge represents the key to developing new anticancer therapies.     

Chimeric antigen receptor (CAR)-engineered lymphocytes for cancer therapy

Introduction: Chimeric antigen receptors (CARs) usually combine the antigen binding site of a monoclonal antibody with the signal activating machinery of a T cell, freeing antigen recognition from MHC restriction and thus breaking one of the barriers to more widespread application of cellular therapy. Similar to treatment strategies employing monoclonal antibodies, T cells expressing CARs are highly targeted, but additionally offer the potential benefits of active trafficking to tumor sites, in vivo expansion and long-term persistence. Furthermore, gene transfer allows the introduction of countermeasures to tumor immune evasion and of safety mechanisms.

Areas covered: The basic structure of so-called first and later generation CARs and their potential advantages over other immune therapy systems. How these molecules can be grafted into immune cells (including retroviral and non-retroviral transduction methods) and strategies to improve the in vivo persistence and function of immune cells expressing CARs. Examples of tumor-associated antigens that have been targeted in preclinical models and clinical experience with these modified cells. Safety issues surrounding CAR gene transfer into T cells and potential solutions to them.

Expert opinion: Because of recent advances in immunology, genetics and cell processing, CAR-modified T cells will likely play an increasing role in the cellular therapy of cancer, chronic infections and autoimmune disorders.     

Immunoregulatory effects of Lactococcus lactis‐derived extracellular vesicles in allergic asthma

BackgroundProbiotics have been shown to prevent various allergic diseases by producing extracellular vesicles (EVs). However, the role of EVs in allergic asthma has not yet been completely determined.MethodsGut microbial composition, mainly genera related to probiotics, was investigated in allergic asthmatic mice. Moreover, EVs were isolated from Lactococcus lactis (L. lactis, a selected bacterium) and EV proteins were identified by peptide mass fingerprinting. EV functions in immune responses were evaluated in vivo or ex vivo. Furthermore, the levels of specific IgG antibodies (an alternative marker for EV quantification) to L. lactis‐EVs were measured by ELISA in the sera of 27 asthmatic patients and 26 healthy controls.ResultsAllergic asthmatic mice showed a lower proportion of Lactococcus compared to healthy mice. L. lactis was cultured and its EVs abundantly contained pyruvate kinase. When allergic asthmatic mice were intranasally treated with EVs, airway hyperresponsiveness, eosinophil number, cytokine secretion, and mucus production were significantly decreased. Moreover, L. lactis‐EV treatment shifted immune responses from Th2 to Th1 by stimulating dendritic cells to produce IL‐12. In addition, significantly lower levels of serum specific IgG4 (but not IgG1) to L. lactis‐EVs were noted in asthmatic patients than in healthy controls. A positive correlation between the levels of EV‐specific IgG4 and FEV₁ (%), but a negative correlation between the levels of EV‐specific IgG4 and IL‐13 were observed.ConclusionThese findings suggest that L. lactis‐EVs may have immune‐regulating effects on airway inflammation mediated by dendritic cell activation, providing a potential benefit for allergic asthma.     

DC-CIK as a widely applicable cancer immunotherapy

ABSTRACT

Introduction: Immunotherapy is now a standard treatment for many malignancies. Although immune checkpoint inhibition has demonstrated substantial efficacy by enhancing T cell activation and function in the tumor microenvironment, adoptive transfer of T and NK cell products promises to provide activated cells capable of immediate and direct tumor destruction. A widely applicable, non-MHC dependent, cellular therapy, consisting of in vitro generated dendritic cells (DC) combined with cytokine-induced killer cells (CIK), is highly efficient to produce from individual patients and has demonstrated safety and efficacy alone or with chemotherapy.

Areas covered: We summarize the clinical data from studies of DC-CIK and discuss future research directions.

Expert opinion: Patients with a wide variety of tumor types who have received DC-CIK therapy may experience clinical responses. This versatile therapy synergizes with other anti-cancer therapies including chemotherapy and immunotherapy.     

Oligonucleotide based-strategies for allergy with special reference to siRNA

Background: Allergic diseases are a significant global health care problem. Current pharmacological approaches address symptoms but do not alter the underlying immune dysregulation. Current allergen-specific immunotherapy has several drawbacks. Therefore, approaches that attenuate allergic responses safely and effectively at the level of upstream causative events are desirable. Oligonuleotide-based therapies [CpG DNA, antisense oligonucleotides, and small interfering RNA (siRNA)] are promising approaches. Objective/methods: We review developments in oligonucleotide-based therapies and the potential of siRNA for treating allergy. Results/conclusions: Strategies with oligonucleotides basically aim to reduce T helper type 2 (Th2) responses. It is controversial whether the reduction of Th2 responses does, in fact, attenuate allergic diseases. Increased understanding of allergic mechanisms will enhance the efficacy of oligonucleotide-based therapy     

Tits and bits of HIV Tat protein

Introduction: HIV-Tat protein displays an array of functions that are essential for HIV replication. The structural flexibility of Tat protein has been regarded as one of the unique features responsible for sustaining diverse functions, from facilitated membrane-crossing ability to strong affinity for RNA binding.

Areas covered: RNA binding ability and presence of multiple interacting domains in the same protein are very important properties of HIV-Tat protein. Tat protein has shown great ability to influence cellular and viral gene expression. We discuss the functions of HIV Tat protein, describing its structural significance, secretion and uptake of HIV Tat protein by immune cells, post-translational modifications and role of HIV Tat protein in HIV pathogenesis.

Expert opinion: Perturbation in expression of many cytokines and chemokines by HIV-Tat protein exhibits downstream immune suppressive function as well as activation of several apoptotic genes. This explains the massive death of immune cells due to bystander effect of HIV Tat protein among HIV-infected patients.     

Targeting human inducible regulatory T cells (Tr1) in patients with cancer: blocking of adenosine–prostaglandin E2 cooperation

Introduction: Emerging data suggest that human inducible regulatory T cells (Tr1) produce adenosine and prostaglandin E₂ and that these factors cooperate in mediating immune suppression.

Areas covered: Human Tr1 present in human tumors or blood of cancer patients express ectonucleotidases, CD39 and/or CD73, hydrolyze ATP to adenosine and are COX-2 positive. Expression of CD39 and/or CD73 on human tumors favors expansion and suppressor functions of Tr1. Adenosine and PGE₂ signal via adenosine 2A receptor (A_2AR) and prostaglandin E₂ receptor 2 (EP₂R) expressed on effector T (Teff) cells, suppressing their anti-tumor functions by a common mechanism involving upregulation of cytosolic cAMP levels and protein kinase A (PKA) type I activation. The frequency and activity of circulating CD4⁺CD39⁺ and CD4⁺COX-2⁺ Treg subsets increase in advanced disease and also following oncologic therapies.

Expert opinion: Pharmacologic blocking of adenosine–PGE₂ collaboration provides a clinically-feasible strategy for disarming of Treg. Used in conjunction with conventional anti-cancer drugs or immune interventions, pharmacologic inhibitors could improve outcome of oncologic therapies.     

Bispecific antibodies engage T cells for antitumor immunotherapy

Introduction: Although considerable evidence supports the hypothesis that T cells play a critical role in the immune response against cancer, the ability to mount and sustain tumor-specific cellular responses in vivo remains a challenge. A strategy that harnesses the cytotoxic advantage of T cell therapy is the use of bispecific antibodies designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex, but only in the presence of a tumor antigen. While antibody constructs with dual specificity were first described as anticancer therapeutics over 25 years ago, it was not until recently that one subclass of bispecific single-chain antibody, the bispecific T cell engager (BiTE), emerged as superior to previous iterations in achieving efficacy in animal models and early clinical trials.

Areas covered: The evolution of bispecific antibodies in antitumor immunotherapy is reviewed and the greatest hurdles impeding their clinical translation are discussed, specifically in the context of immunoprivileged sites as is the case for intracerebral malignancy.

Expert opinion: The BiTE platform has great potential in the treatment of malignant disease. Despite burgeoning interest in bispecific antibodies and permutations thereof, the issues of stability and cost-effective production persist as obstacles.     

Modulation of toll-like receptor function has therapeutic potential in autoimmune disease

Importance of the field: The role of toll-like receptors (TLRs) in the immune response to exogenous pathogens is well characterized. These receptors have been suggested to be involved in the initiation and/or perpetuation of many inflammatory autoimmune diseases and have become attractive candidates for the modulation of inflammation.

Areas covered in this review: This review discusses the evidence to support a potential role for TLRs in inflammatory diseases, focusing on rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. The approaches to targeting TLR activation are outlined.

What the reader will gain: An appreciation for the role of TLRs in inflammatory diseases and in particular the contribution of specific TLRs in rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. This review focuses on recent developments in targeting TLR activity from ligand binding through to the resultant signaling.

Take home message: As initiators of immune responses, TLRs have previously been targeted to increase the immune response with some success. However, targeting TLRs to attenuate immune responses for the treatment of chronic inflammatory diseases will require further evidence of the mechanisms of TLR involvement in the pathophysiology and a better understanding of the potential effects of modulating TLR physiology over a sustained period.