Induction Of Cellular Immunity Research Articles

Effects of the induction of humoral and cellular immunity by third vaccination for SARS-CoV-2

IntroductionTo control the spread of severe disease caused by mutant strains of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), it is necessary to determine whether continued vaccination enhances humoral and cellular immunity. AimIn this study, we examined the changes in humoral and cellular immunity to SARS-CoV-2 after administration of the third vaccination in Japanese adults who had received the second dose of messenger ribonucleic acid (mRNA)-1273 vaccine and the third vaccination (BNT162b2 or mRNA-1273). MethodsWe measured anti-spike antibodies in immunoglobulin G (IgG) and anti-nucleocapsid IgG titers in the serum of the vaccinated subjects. To evaluate cellular immunity, the peripheral blood mononuclear cells of inoculated individuals were cultured with spiked proteins, including those of the SARS-CoV-2 conventional strain and Omicron strain, and then subjected to enzyme-linked immunospot (ELISPOT). ResultsThe results revealed that the anti-SARS-CoV-2 spike protein antibody titer increased after the third vaccination and was maintained; however, a decrease was observed at 6 months after vaccination. SARS-CoV-2 antigen-specific T helper (Th)1 and Th2 cell responses were also induced after the third vaccination and were maintained for 6 months after vaccination. Furthermore, induction of cellular immunity against Omicron strains by the omicron non-compliant vaccines, BNT162b2 or mRNA-1273, was observed. ConclusionThese findings demonstrate the effectiveness of vaccination against unknown mutant strains that may occur in the future and provide important insights into vaccination strategies.

Preparation of glycopeptide-modified pH-sensitive liposomes for promoting antigen cross-presentation and induction of antigen-specific cellular immunity.

Cross-presentation, exogenous antigen presentation onto major histocompatibility complex class I molecules on antigen presenting cells, is crucially important for inducing antigen-specific cellular immune responses for cancer immunotherapy and for the treatment of infectious diseases. One strategy to induce cross-presentation is cytosolic delivery of an exogenous antigen using fusogenic or endosomolytic molecule-introduced nanocarriers. Earlier, we reported liposomes modified with pH-responsive polymers to achieve cytosolic delivery of an antigen. Polyglycidol-based or polysaccharide-based pH-responsive polymers can provide liposomes with delivery performance of antigenic proteins into cytosol via membrane fusion with endosomes responding to acidic pH, leading to induction of cross-presentation. Mannose residue was introduced to pH-responsive polysaccharides to increase uptake selectivity to antigen presenting cells and to improve cross-presentation efficiency. However, direct introduction of mannose residue into pH-responsive polysaccharides suppressed cytoplasmic delivery performance of liposomes. To avoid such interference, for this study, mannose-containing glycans were incorporated separately into pH-responsive polysaccharide-modified liposomes. Soybean agglutinin-derived glycopeptide was used as a ligand for lectins on antigen presenting cells. Incorporation of glycopeptide significantly increased the cellular uptake of liposomes by dendritic cell lines and increased cross-presentation efficiency. Liposomes incorporated both glycopeptide and pH-responsive polysaccharides exhibited strong adjuvant effects in vitro and induced the increase of dendritic cells, M1 macrophages, and effector T cells in the spleen. Subcutaneous administration of these liposomes induced antigen-specific cellular immunity, resulting in strong therapeutic effects in tumor-bearing mice. These results suggest that separate incorporation of glycopeptides and pH-responsive polysaccharides into antigen-loaded liposomes is an effective strategy to produce liposome-based nanovaccines to achieve antigen cross-presentation and induction of cellular immunity towards cancer immunotherapy.

PH-Sensitive branched β-glucan-modified liposomes for activation of antigen presenting cells and induction of antitumor immunity.

Induction of cellular immunity is important for effective cancer immunotherapy. Although various antigen carriers for cancer immunotherapy have been developed to date, balancing efficient antigen delivery to antigen presenting cells (APCs) and their activation via innate immune receptors, both of which are crucially important for the induction of strong cellular immunity, remains challenging. For this study, branched β-glucan was selected as an intrinsically immunity-stimulating and biocompatible material. It was engineered to develop multifunctional liposomal cancer vaccines capable of efficient interactions with APCs and subsequent activation of the cells. Hydroxy groups of branched β-glucan (Aquaβ) were modified with 3-methylglutaric acid ester and decyl groups, respectively, to provide pH-sensitivity and anchoring capability to the liposomal membrane. The modification efficiency of Aquaβ derivatives to the liposomes was significantly high compared with linear β-glucan (curdlan) derivatives. Aquaβ derivative-modified liposomes released their contents in response to weakly acidic pH. As a model antigenic protein, ovalbumin (OVA)-loaded liposomes modified with Aquaβ derivatives interacted efficiently with dendritic cells, and induced inflammatory cytokine secretion from the cells. Subcutaneous administration of Aquaβ derivative-modified liposomes suppressed the growth of the E.G7-OVA tumor significantly compared with curdlan derivative-modified liposomes. Aquaβ derivative-modified liposomes induced the increase of CD8+ T cells, and polarized macrophages to the antitumor M1-phenotype within the tumor microenvironment. Therefore, pH-sensitive Aquaβ derivatives can be promising materials for liposomal antigen delivery systems to induce antitumor immune responses efficiently.

RNA Vaccines: A Suitable Platform for Tackling Emerging Pandemics?

The COVID-19 pandemic demonstrates the ongoing threat of pandemics caused by novel, previously unrecognized, or mutated pathogens with high transmissibility. Currently, vaccine development is too slow for vaccines to be used in the control of emerging pandemics. RNA-based vaccines might be suitable to meet this challenge. The use of an RNA-based delivery mechanism promises fast vaccine development, clinical approval, and production. The simplicity of in vitro transcription of mRNA suggests potential for fast, scalable, and low-cost manufacture. RNA vaccines are safe in theory and have shown acceptable tolerability in first clinical trials. Immunogenicity of SARS-CoV-2 mRNA vaccines in phase 1 trials looks promising, however induction of cellular immunity needs to be confirmed and optimized. Further optimization of RNA vaccine modification and formulation to this end is needed, which may also enable single injection regimens to be achievable. Self-amplifying RNA vaccines, which show high immunogenicity at low doses, might help to improve potency while keeping manufacturing costs low and speed high. With theoretical properties of RNA vaccines looking promising, their clinical efficacy is the key remaining question with regard to their suitability for tackling emerging pandemics. This question might be answered by ongoing efficacy trials of SARS-CoV-2 mRNA vaccines.

Immunostimulatory effect of chitosan conjugated green copper oxide nanoparticles in tumor immunotherapy

Current study demonstrates the immunogenic role of biopolymer coated green synthesized copper oxide nanoparticles by the induction of cellular immunity through the activation immune cells. Alongside humoral immunity response was triggered by the surface coated NPs through IgG response which indicate the adjuvanic role of the nano conjugate. Th1 (Type 1 and Type 2 helper T cells) and Th2 cells were activated after the treatment with nano conjugate and act as an immunostimulant which would inhibit the proliferation of breast cancer (MCF-7) and cervical cancer (HeLa) cells in in vitro. Solid tumor induced by 4 T1 cells were also inhibited in in vivo Balb/C mice model. Secretion of pro-inflammatory cytokines and the increase in CD + 4 populations indicate the activation of immune cells in the current study. Immunotherapy by the help of metal nano conjugate can be an effective tool to eradicate the cancer cells from the system.

Immunogenicity of a novel tetravalent dengue envelope protein domain III-based antigen in mice.

Dengue virus is a mosquito-borne pathogen that causes dengue diseases. All four serotypes of dengue virus are infectious for humans. Therefore, an efficacious dengue vaccine should be tetravalent to provide protection against all types of virus. The goal of this study was to design a new tetravalent recombinant protein from envelope protein of dengue viruses to induce virus-neutralizing antibodies against all four serotypes in mice. A chimeric protein was designed from domain III of envelope protein of all serotypes of dengue virus. Four domain III fragments were linked together by alpha helix making linkers. The final sequence of the designed protein was analyzed in silico and the coding gene sequence was deduced by reverse translation. After cloning and expression of the recombinant protein (ED3-tetravalent protein), identity of the purified protein was confirmed using a pan-dengue specific monoclonal antibody in Western blotting. Then, the immunogenicity of the purified protein was studied in mice using antibody titration. The efficacy of induced antibodies in neutralization of the virus was studies by FRNT method. Furthermore, the induction of cellular immunity was studied by measurement of cytokines using ELISA method and measurement of lymphocyte proliferation using MTT assay. The ED3-tetravalent protein was able to enhance neutralizing immunogenic response against all four dengue serotypes; in similar way to that of tetravalent formulation of four individual domain III-based polypeptides. It is suggested that the ED3-tetravalent fusion protein can induce broadly neutralizing antibody responses against all four serotypes of dengue virus in mice.

Induction of humoural and cellular immunity by immunisation with HCV particle vaccine in a non-human primate model

ObjectiveAlthough HCV is a major cause of chronic liver disease worldwide, there is currently no prophylactic vaccine for this virus. Thus, the development of an HCV vaccine that can induce...

Human Anti-CD40 Antibody and Poly IC:LC Adjuvant Combination Induces Potent T Cell Responses in the Lung of Nonhuman Primates.

Nonlive vaccine platforms that induce potent cellular immune responses in mucosal tissue would have broad application for vaccines against infectious diseases and tumors. Induction of cellular immunity could be optimized by targeted activation of multiple innate and costimulatory signaling pathways, such as CD40 or TLRs. In this study, we evaluated immune activation and elicitation of T cell responses in nonhuman primates after immunization with peptide Ags adjuvanted with an agonistic anti-CD40Ab, with or without the TLR3 ligand poly IC:LC. We found that i.v. administration of the anti-CD40Ab induced rapid and transient innate activation characterized by IL-12 production and upregulated costimulatory and lymph node homing molecules on dendritic cells. Using fluorescently labeled Abs for in vivo tracking, we found that the anti-CD40Ab bound to all leukocytes, except T cells, and disseminated to multiple organs. CD4(+) and CD8(+) T cell responses were significantly enhanced when the anti-CD40Ab was coadministered with poly IC:LC compared with either adjuvant given alone and were almost exclusively compartmentalized to the lung. Notably, Ag-specific T cells in the bronchoalveolar lavage were sustained at ∼5-10%. These data indicate that systemic administration of anti-CD40Ab may be particularly advantageous for vaccines and/or therapies that require T cell immunity in the lung.

HPV-Specific Immunotherapy: Key Role for Immunomodulators

Cervical cancer is the second most common malignancy among women worldwide. The prime causal factor of the disease is a persistent infection with human papillomavirus (HPV) with individuals failing to mount a sufficient immune response against the virus. Despite the current success of HPV16- and 18-specific prophylactic vaccination, established HPV infections and associated neoplasia require therapeutic vaccines with the induction of cellular immunity. The sustained expression of early proteins E6 and E7 from major oncogenic HPV genotypes in cervical lesions are ideal targets for the design of immunotherapeutic strategies. These strategies, particularly subunit vaccines, may require additional help from immunomodulators to enhance HPV-specific cellular responses. This review discusses recent studies, published since 2008, relating to immunotherapeutic strategies against HPV that include immunomodulators. These immunomodulators fall within the category of toll-like receptor adjuvants for innate immune activation, adjuvants directly contributing to adaptive immunity, such as cytokines and costimulatory molecules, and those that target tumor-induced immunosuppressive mechanisms. Using a combination of these strategies with delivery-based approaches may be most beneficial for the success of therapeutic vaccines against HPV-induced neoplasia in the clinic.

Immunotherapy with FBTA05 (Bi20), a trifunctional bispecific anti-CD3 x anti-CD20 antibody and donor lymphocyte infusion (DLI) in relapsed or refractory B-cell lymphoma after allogeneic stem cell transplantation: study protocol of an investigator-driven, open-label, non-randomized, uncontrolled, dose-escalating Phase I/II-trial

BackgroundPatients with B cell malignancies refractory to allogeneic stem cell transplantation (SCT) can be treated by subsequent immunotherapy with donor lymphocyte infusions (DLI). But unlike myeloid leukemia, B cell leukemia and lymphoma are less sensitive to allogeneic adoptive immunotherapy. Moreover, the beneficial graft-versus-lymphoma (GVL) effect may be associated with moderate to severe graft-versus-host disease (GVHD). Thus, novel therapeutic approaches augmenting the anti-tumor efficacy of DLI and dissociating the GVL effect from GVHD are needed. The anti-CD20 x anti-CD3 trifunctional bispecific antibody (trAb) FBTA05 may improve the targeting of tumor cells by redirecting immune allogeneic effector cells while reducing the risk of undesirable reactivity against normal host cells. Hence, FBTA05 may maximize GVL effects by simultaneously decreasing the incidence and severity of GVHD.Methods/DesignBased on this underlying treatment concept and on promising data taken from preclinical results and a small pilot study, an open-label, non-randomized, uncontrolled, dose-escalating phase I/II-study is conducted to evaluate safety and preliminary efficacy of the investigational antibody FBTA05 in combination with DLI for patients suffering from rituximab- and/or alemtuzumab-refractory, CD20-positive low- or high-grade lymphoma after allogeneic SCT. During the first trial phase with emphasis on dose escalation a maximum of 24 patients distributed into 4 cohorts will be enrolled. For the evaluation of preliminary efficacy data a maximum of 12 patients (6 patients with low-grade lymphoma and/or Chronic Lymphocytic Leukemia (CLL) / 6 patients with high-grade or aggressive lymphoma) will attend the second phase of this clinical trial.DiscussionPromising data (e.g. induction of cellular immunity; GVL predominance over GVHD; achievement of partial or complete responses; prolongation of time-to-progression) obtained from this phase I/II trial would represent the first milestone in the clinical evaluation of a novel immunotherapeutic concept for treatment-resistant low- and high-grade lymphoma and NHL patients in relapse.Trial registrationNCT01138579

The role of IL-17 in modulation of antitumour immunity and progression of colitis-associated cancer

Colorectal carcinoma is one of the most frequent malignancies worldwide. There is a strong belief that it is initiated in the inflammatory bowel disease microenvironment. Pro-inflammatory cytokines produced by malignant cells as well as by tumor infiltrating leukocytes facilitate origination, growth and progression of cancer. An important role of T cells in antitumor immunity is well established. CD4+ Th lymphocytes can be classified into a few functional phenotypes: T helper 1 (Th1), T helper 2 (Th2), T helper 17 (Th17), according to the ability to secrete different cytokines. Th1 lymphocytes play important role in induction of cellular immunity, while Th2 lymphocytes suppress cellular immunity and enhance humoral immune response. Th17 lymphocytes are the key players in inducing inflammation by recruitment of neutrophils and macrophages. The polarization of T-mediated immune response has multiple effects on tumor progression. Although Th2-type cytokines can induce acute tumor rejection, Th1- type cytokines provide a greater antitumor effect and can promote durable anti-tumor CD8+T cell response. However, the role of IL-17 in pathogenesis of colitis-associated cancer (CAC) has not been fully understood. The aim of this paper is to clarify the role of IL-17 in modulation of antitumor immunity and progression of colorectal carcinoma.

ChAd63-MVA–vectored Blood-stage Malaria Vaccines Targeting MSP1 and AMA1: Assessment of Efficacy Against Mosquito Bite Challenge in Humans

The induction of cellular immunity, in conjunction with antibodies, may be essential for vaccines to protect against blood-stage infection with the human malaria parasite Plasmodium falciparum. We have shown that prime-boost delivery of P. falciparum blood-stage antigens by chimpanzee adenovirus 63 (ChAd63) followed by the attenuated orthopoxvirus MVA is safe and immunogenic in healthy adults. Here, we report on vaccine efficacy against controlled human malaria infection delivered by mosquito bites. The blood-stage malaria vaccines were administered alone, or together (MSP1+AMA1), or with a pre-erythrocytic malaria vaccine candidate (MSP1+ME-TRAP). In this first human use of coadministered ChAd63-MVA regimes, we demonstrate immune interference whereby responses against merozoite surface protein 1 (MSP1) are dominant over apical membrane antigen 1 (AMA1) and ME-TRAP. We also show that induction of strong cellular immunity against MSP1 and AMA1 is safe, but does not impact on parasite growth rates in the blood. In a subset of vaccinated volunteers, a delay in time to diagnosis was observed and sterilizing protection was observed in one volunteer coimmunized with MSP1+AMA1-results consistent with vaccine-induced pre-erythrocytic, rather than blood-stage, immunity. These data call into question the utility of T cell-inducing blood-stage malaria vaccines and suggest that the focus should remain on high-titer antibody induction against susceptible antigen targets.

Incorporation of polyinosine–polycytidylic acid enhances cytotoxic T cell activity and antitumor effects by octaarginine-modified liposomes encapsulating antigen, but not by octaarginine-modified antigen complex

In a previous study, we reported on the efficient delivery of an antigen to the cytosol and a specific-antigen presentation on MHC class I in dendritic cells by rationally controlling the intracellular trafficking of ovalbumin (OVA), a model antigen, with stearylated octaarginine-modified liposomes (R8-Lip/OVA). However, no significant difference in antitumor effects against E.G7-OVA, OVA expressed lymphoma, was observed between R8-Lip/OVA and an electrostatic complex of R8 and OVA (R8/OVA-Com). In this study, we hypothesized that use of adjuvants clarified the difference in immune responses between R8-Lip/OVA and R8/OVA-Com, and selected polyinosine-polycytidylic acid (polyI:C) as an adjuvant. Cytotoxic T lymphocyte (CTL) activity of the polyI:C and OVA encapsulated R8-Lip (R8-Lip/PIC/OVA) was drastically enhanced compared to R8-Lip/OVA and complete Freund's adjuvant with OVA. Moreover, the incorporation of polyI:C clearly was critical for the difference in antitumor effects and CTL activities between R8-Lip/OVA and R8/OVA-Com. These findings suggest that the carriers that are incorporated polyI:C has a great influence on the induction of cellular immunity in vivo.

New insights in mucosal vaccine development

Mucosal surfaces are the major entrance for infectious pathogens and therefore mucosal immune responses serve as a first line of defence. Most current immunization procedures are obtained by parenteral injection and only few vaccines are administered by mucosal route, because of its low efficiency. However, targeting of mucosal compartments to induce protective immunity at both mucosal sites and systemic level represents a great challenge. Major efforts are made to develop new mucosal candidate vaccines by selecting appropriate antigens with high immunogenicity, designing new mucosal routes of administration and selecting immune-stimulatory adjuvant molecules. The aim of mucosal vaccines is to induce broad potent protective immunity by specific neutralizing antibodies at mucosal surfaces and by induction of cellular immunity. Moreover, an efficient mucosal vaccine would make immunization procedures easier and be better suited for mass administration. This review focuses on contemporary developments of mucosal vaccination approaches using different routes of administration.

Identification of broad binding class I HLA supertype epitopes to provide universal coverage of influenza A virus

Influenza virus remains a significant health concern, with current circulating strains that affect millions each year plus the threat of newly emerging strains, such as swine-origin H1N1 and avian H5N1. Our hypothesis is that influenza-derived HLA-class I–restricted epitopes can be identified for use as a reagent to monitor and quantitate human CD8 + T-cell responses and for vaccine development to induce protective cellular immunity. Protein sequences from influenza A virus strains currently in circulation, agents of past pandemics and zoonotic infections of man were evaluated for sequences predicted to bind to alleles representative of the most frequent HLA-A and -B (class I) types worldwide. Peptides that bound several different HLA molecules and were conserved among diverse influenza subtypes were tested for their capacity to recall influenza-specific immune responses using human donor PBMC. Accordingly, 28 different epitopes antigenic for human donor PBMC were identified and 25 were 100% conserved in the newly emerged swine-origin H1N1 strain. The epitope set defined herein should provide a reagent applicable to quantitate CD8 + T cell human responses irrespective of influenza subtype and HLA composition of the responding population. In addition, these epitopes may be suitable for vaccine applications directed at the induction of cellular immunity.

Effect of immunological adjuvants: GM-CSF (granulocyte-monocyte colony stimulating factor) and IL-23 (interleukin-23) on immune responses generated against hepatitis C virus core DNA vaccine

The use of cytokines as adjuvants has been shown to be a promising approach for enhancing DNA vaccine induced-immune responses. In this report, we investigate the administration of cytokines to modulate both humoral and cell-mediated immune responses elicited by an HCV-core plasmid DNA vaccine in Balb/c mice. Our studies indicate that the HCV-core DNA vaccine has been able to induce both antibody and cellular immunity in a DNA prime-protein boost regimen. GM-CSF (granulocyte-monocyte colony stimulating factor) which is considered to be a cytokine displaying both Th1 and Th2 characteristics, and plays an important role in augmenting antibody and cell-mediated immunity was also administered. The induction of cellular immunity was not as striking as humoral immunity in this case. To obtain a stronger cellular response, IL-23, a Th1 cytokine belonging to the IL-12 family, was also included in the regimen. Spleen cell proliferation, IFN-γ production from spleen cells and specific serum IgG2a, all demonstrate the enhancement of cell-mediated immunity without any observable suppressive effect on antibody and humoral immune responses. We also examined the timing of plasmid IL-23 administration on the phenotype of the resultant T cell responses in a 3 day interval, before and after plasmid GM-CSF administration. The results did not indicate any change in theTh1/Th2 balance as compared with simultaneous IL-23 administration.

Vaccination Against VEGFR2 Attenuates Initiation and Progression of Atherosclerosis

Vascular endothelial growth factor receptor 2 (VEGFR2)-overexpressing cells may form an interesting target for the treatment of atherosclerosis because of their involvement in processes that contribute to this disease, such as angiogenesis. We vaccinated mice against VEGFR2 by an orally administered DNA vaccine, comprising a plasmid, encoding murine VEGFR2, carried by live attenuated Salmonella typhimurium. This vaccine induces cellular immunity against cells that overexpress VEGFR2. Vaccination of hypercholesterolemic mice against VEGFR2 resulted in a marked induction of CD8+ cytotoxic T cells specific for VEGFR2 and led to an inhibition of angiogenesis in a hindlimb ischemia model. Interestingly, VEGFR2 vaccination attenuated the progression of preexisting advanced atherosclerotic lesions in the brachiocephalic artery of apoE-/- mice. Furthermore, VEGFR2 vaccination strongly reduced the initiation of collar-induced atherosclerosis in the carotid arteries of LDLr-/- mice. In addition, denudation of the carotid artery, as a model for postinterventional lesion formation, resulted in delayed endothelial replacement and significantly increased neointima formation on VEGFR2 vaccination. These data indicate the prominent role of VEGFR2+ cells in cardiovascular diseases and show that induction of cellular immunity against atherosclerosis-associated cells by means of DNA vaccination may contribute to the development of novel therapies against atherosclerosis.

Uptake of Human Papillomavirus Virus-Like Particles by Dendritic Cells Is Mediated by Fcγ Receptors and Contributes to Acquisition of T Cell Immunity

Chimeric human papillomavirus virus-like particles (HPV cVLP) are immunogens able to elicit potent CTL responses in mice against HPV16-transformed tumors; however, the mechanism of T cell priming has remained elusive. HPV VLP bind to human MHC class II-positive APCs through interaction with FcgammaRIII, and immature dendritic cells (DC) become activated after incubation with HPV VLP; however, it is unclear whether FcgammaR on DC are involved. In mice, FcgammaRII and FcgammaRIII are homologous and bind similar ligands. In this study, we show that binding and uptake of VLP by DC from FcgammaRII, FcgammaRIII, and FcgammaRII/III-deficient mice are reduced by up to 50% compared with wild-type mice. Additionally, maturation of murine DC from FcgammaRII/III-deficient mice by VLP is also reduced, indicating that DC maturation, and thus Ag presentation, is diminished in the absence of expression of FcgammaR. To investigate the in vivo contribution of FcgammaR in the induction of cellular immunity, FcgammaR single- and double-knockout mice were immunized with HPV16 L1/L2-E7 cVLP, and the frequency of E7-specific T cells was analyzed by tetramer binding, IFN-gamma ELISPOT, and cytotoxicity assays. All readouts indicated that the frequency of E7-specific CD4(+) and CD8(+) T cells induced in all FcgammaR-deficient mice after immunization with cVLP was significantly diminished. Based on these results, we propose that the low-affinity FcgammaR contribute to the high immunogenicity of HPV VLP during T cell priming by targeting VLP to DC and inducing a maturation state of the DC that facilitates Ag presentation to and activation of naive T cells.

A blowfly strike vaccine requires an understanding of host–pathogen interactions

The phase-out of Mulesing by 2010 means the Australian wool industry requires immediate and viable alternatives for the control and prevention of blowfly strike, an economically important parasitic disease of sheep. In this review we have analysed previous research aimed toward the development of a vaccine against blowfly strike and the reasons why the approaches taken were unsuccessful at the time. Close scrutiny has provided new insight into this host-parasite interaction and identified new opportunities for the development of a vaccine. Here we propose that addressing immunosuppression together with the induction of cellular immunity is likely to result in an anti-blowfly strike vaccine, as opposed to the use of "standard" approaches aimed at inducing humoral immunity.

Induction of cellular immunity against hair follicle melanocyte causes alopecia

Alopecia areata (AA) is generally regarded as an organ-specific autoimmune disease. Although it has been hypothesized that the autoimmunity is mediated by T cells and that hair follicle melanocyte is one of the targets, definitive evidence is lacking. We here demonstrate that AA-like lesions can be induced in mice by inducing CD8(+) T-cell-mediated immunity to hair follicle melanocytes. We found that hair loss was induced in mice-bearing interleukin-12-producing B16 melanoma cells by the depletion of CD4(+) T cells, accompanied by vitiligo-like coat color change. The alopecic lesions varied in size from pachy to extensive. In many instances, hair loss developed and was followed by the regrowth of white hairs. Histological analysis revealed that mononuclear cells infiltrated in and around the bulb region of hair follicles. Furthermore, immunohistochemical examination clearly showed the intra-follicular infiltration of CD8(+) T cells. Neither the vitiligo-like coat color nor AA-like lesions were induced when CD8(+) T cells were codepleted. These observations indicate that the induction of CD8(+) T-cell-mediated immunity against hair follicle melanocytes causes alopecia. It is thought that there are many types of AA with different mechanisms, targets etc. Although hair follicle melanocytes have long been thought to be one of the targets of AA, evidence to support the hypothesis is sparse. Therefore, we believe that our observation is significant to support the hypothesis.