Suppression of intrinsic B-cell function in Dengue-infected mice.

Mice infected with Dengue virus show a depressed immune response to lipopolysaccharide (LPS), a helper T-cell-independent antigen, when LPS was administered on day 0, 6 and 12 post infection. Mice injected with inactivated virus failed to show immunosuppression.     

CD1d and natural T cells: how their properties jump-start the immune system

Cellular and humoral immune mechanisms recruited to defend the host from infectious agents depend upon the early immune events triggered by antigen. The cytokine milieu within which the immune response matures is the most important of many factors that govern the nature of the immune response. Natural T cells, whose function is controlled by CD1d molecules, are an early source of cytokines that can bestow type 1 or type 2 differentiative potential upon helper T lymphocytes. This review attempts to illuminate the glycolipid antigen presentation properties of CD1d, how CD1d controls the function of natural T cells and how CD1d and natural T cells interact to jump start the immune system. CD1d is postulated to function as a sensor, sensing alterations in cellular lipid content by virtue of its affinity for such ligands. The presentation of a neo-self glycolipid, presumably by infectious assault of antigen-presenting cells, activates natural T cells, which promptly release pro-inflammatory and anti-inflammatory cytokines and jumpstart the immune system. Received 10 July 2000; received after revision 16 October 2000, accepted 16 November 2000     

The translocation motif of hepatitis B virus improves protein vaccination

Cell-penetrating peptides (CPPs) have been shown to improve antigen loading of dendritic cell vaccines. Here we asked whether fusion of a CPP to a protein improves its immunogenicity when this fusion protein is directly applied as vaccine. We used the cell-penetrating translocation motif (TLM) derived from the hepatitis B virus, because no size limitation of cargos has been observed. Increased immunogenicity was observed when TLM was fused to ovalbumin (TLM-ova). TLM-ova was found to be superior to ova in inducing proliferation and cytotoxicity of ova-specific CD8+ T cells in vitro and in vivo. Using ovalbumin-expressing thymoma cells (EG7-ova), an improved anti-tumor immune response was observed for TLM-ova vaccination versus vaccination with ova. Moreover, TLM-ova vaccination induced a higher titer of anti-ovalbumin IgG2a antibodies compared to ova. These data demonstrate that CPP-protein vaccines can improve cellular as well as humoral immune responses. Received 16 November 2005; received after revision 12 December 2005; accepted 10 January 2006 †These authors contributed equally to this work     

Heat shock proteins in immune response to cancer: The Fourth Paradigm

The involvement of heat shock proteins in immune response is categorized into four distinct paradigms. In the First Paradigm, HSP derived from foreign organisms act as classical foreign antigens, and they elicit immune response to the non-conserved HSP epitopes. The Second Paradigm refers to instances where the host responds to self HSP to which there is no central or peripheral tolerance. The Third Paradigm involves molecular mimicry, where cross-reactivity between an HSP and another protein leads to an immune response to the latter under conditions which elicit an immune response to the former, such as infection with a bacterium whose immunodominant antigen is an HSP. The Fourth Paradigm refers to situations where an HSP-antigen complex elicits an effective response to the antigen andnot to the HSP. Thus the HSP acts as a carrier for the antigenic peptide. The role of HSP in recognition by γδ T cells may also fall into this paradigm. In this article, the Fourth Paradigm is considered as a crucial element in the development of vaccines against cancers and infectious diseases, and is analyzed through the prism of the observed association of hsp70 species with antigenic peptides.     

Immune responses to DNA vaccines

DNA vaccines, based on plasmid vectors expressing an antigen under the control of a strong promoter, have been shown to induce protective immune responses to a number of pathogens, including viruses, bacteria and parasites. They have also displayed efficacy in treatment or prevention of cancer, allergic diseases and autoimmunity. Immunologically, DNA vaccines induce a full spectrum of immune responses that include cytolytic T cells, T helper cells and antibodies. The immune response to DNA vaccines can be enhanced by genetic engineering of the antigen to facilitate its presentation to B and T cells. Furthermore, the immune response can be modulated by genetic adjuvants in the form of vectors expressing biologically active determinants or by more traditional adjuvants that facilitate uptake of DNA into cells. The ease of genetic manipulation of DNA vaccines invites their use not only as vaccines but also as research tools for immunologists and microbiologists. Received 26 October 1998; received after revision 3 December 1998; accepted 3 December 1998     

The macromolecular peptide-loading complex in MHC class I-dependent antigen presentation

A challenging task for the adaptive immune system of vertebrates is to identify and eliminate intracellular antigens. Therefore a highly specialized antigen presentation machinery has evolved to display fragments of newly synthesized proteins to effector cells of the immune system at the cell surface. After proteasomal degradation of unwanted proteins or defective ribosome products, resulting peptides are translocated into the endoplasmic reticulum by the transporter associated with antigen processing and loaded onto major histocompatibility complex (MHC) class I molecules. Peptide-MHC I complexes are transported via the secretory pathway to the cell surface where they are then inspected by cytotoxic T lymphocytes, which can trigger an immune response. This review summarizes the current view of the intracellular machinery of antigen processing and of viral immune escape mechanisms to circumvent destruction by the host. Received 4 October 2005; received after revision 19 November 2005; accepted 24 November 2005     

Effect of periodate oxidation of glycoconjugates of lymphocyte membranes on the immune response in vitro]

Mouse spleen cells treated with sodium periodate for 10 min. at 4 degrees C are stimulated to undergo blastogenesis and to incorporate thymidine. The effect of such treatment on the antibody response in vitro induced by Sheep red blood cells has been evaluated. Periodate-induced proliferation is accompanied by a marked inhibition of the immune response to this antigen. At concentrations leading to mitogenesis, no cytotoxic effect of periodate was observed and treated cells survived well on tissue culture. Cell recoveries from samples treated with periodate at the optimal mitogenic dose, were markedly enhanced when harvested at different days after culturing wheras lower antibody forming cells numbers wereconsistently observed during the culture period.     

Modulation of antibody synthesis by an anti-tumour alga

Summary An unicellular alga,Chlorella pyrenoidosa, which had been reported to protect C₃H mice against sarcoma BP8, is shown, when injected in Freund's incomplete adjuvant, to modulate the antibody synthesis induced by immunization with a hapten-carrier complex.C. pyrenoidosa appeared to be able to initiate an antigenic competition between hapten and carrier determinants of the antigen molecule during antibody synthesis, and thus it could be speculated thatC. pyrenoidosa modulates the immune response at the macrophage level.Acknowledgments. This work was supported by the Secrétariat d'Etat aux Universités and by the DGRST, grant No. 77.71347.     

Induction of immunological memory in mice by RNA extract

Summary RNA extract isolated from spleens of mice immunized with lipopolysaccharide fromE. coli induced an immunological memory in normal mice. Application of small amounts of corresponding antigen provoked a specific secondary immune response in RNA primed mice.     

Receptors for cytomegaloviruses on the surface of human lymphocytes]

The relationships between cytomegalovirus (CMV) and lymphocytes have already been noted because of: (a) the immunological abnormalities induced by this virus, and (b) activation of latent CMV in the course of lymphocyte reactions associated with anti-histocompatibility antigen immune response. The present work shows that the lymphocyte surface may have specific receptors for CMV. Cultured fibroblasts infected with DMV were incubated with lymphocytes isolated from the blood of human immune subjects. Rosettes defined by the adherence of three or more lymphocytes around a fibroblast were formed in infected preparation while no rosettes were seen with normal control fibroblasts. Approximately 1.2 per cent of lymphocytes were involved in the formation of these rosettes. Rosette formation is inhibited when infected fibroblasts have been incubated with anti-CMV antibodies prior to the addition of lymphocytes.     

Evidence for suppression of immune function by insulin-like growth factor-1 in dwarf rats in vivo

These studies were undertaken to investigate the effects of increasing or decreasing IGF-1 levels on aspects of immune function in rats. Female dwarf rats were treated with recombinant human IGF-1 or with a potent sheep anti-IGF-serum. Body weight, thymus weight and spleen weight increased with IGF-1 treatment (p<0.001), while there was no effect of anti-IGF-1 treatment when compared with the appropriate normal sheep serum (NSS) treated controls. IGF-1 treatment significantly decreased WBC and RBC counts, but increased the ratio of CD4⁺:CD8⁺ T-cells. Anti-IGF-1 serum had no effect on these parameters compared with NSS. However anti-IGF-1 was associated with increased T-cell numbers, decreased natural killer cells, and enhancement of the animals' ability to produce specific IgG in response to injection of keyhole limpet haemocyanin (KLH). These results indicate that IGF-1 may suppress immune function although increasing the size of immune organs such as spleen.These studies were part of an M.Sc. at the University of Waikato, Hamilton, New Zealand.     

<Emphasis Type="Italic">The Art of War:</Emphasis> Innate and adaptive immune responses

Research over the last several years has greatly advanced our understanding of the mechanisms by which the immune system functions. There exist two main branches of immunity, termed innate and adaptive immunity. Innate immunity uses the genetic memory of germline-encoded receptors to recognize the molecular patterns of common pathogens. Adaptive immunity, akin to somatic memory, is a complex system by which the body learns to recognize a pathogens unique antigens and builds an antigen specific response to destroy it. The effective development of the overall immune response depends on careful interplay and regulation between innate and adaptive immunity. Here we review our current understanding of how these integrated systems distinguish targets against which a response is appropriate and neutralize potentially pathogenic challenges.Received 8 May 2003; accepted 2 June 2003     

Generalized immunosuppression: how viruses undermine the immune response

Following infection, a virus must battle against the host's immune response. Viruses have developed many ways to escape immune surveillance and downregulate the host's immune response. Some viruses cause a generalized immunosuppression, thereby inhibiting or depressing the immune response towards themselves as well as towards unrelated pathogens. This review will focus on the mechanisms involved in the three main human viral infections causing immunosuppression: measles, human immunodeficiency virus and cytomegalovirus. We will also discuss what has been learned from the extensively studied mouse models of viral-induced immunosuppression: lymphocytic choriomeningitis virus and Rauscher leukemia virus. All of these viruses that induce generalized immunosuppression appear to do so by very similar mechanisms. They hinder antigen presentation to T cells and/or hematopoiesis. We will highlight the similarities in the viral targets as well as present evidence for alternate mechanisms.     

Human peripheral blood monuclear cells transfected with messenger RNA stimulate antigen-specific cytotoxic T-lymphocytes in vitro

The efficiency of test vaccines needs to be evaluated by quantification of the triggered cellular immune response. Usually, for these assays, autologous target cells expressing the vaccine antigen are required. In the context of messenger RNA (mRNA)-based vaccinations, the target cells used for the read-out are mRNA-transfected monocyte-derived dendritic cells (Mo-DCs). Their production typically requires samples of 100 ml blood from the patients, and limits the number of assays that can be performed. We show here that fresh peripheral blood mononuclear cells (PBMCs) can be transfected with mRNA by electroporation. Such cells are as efficient as mRNA-transfected Mo-DCs for their ability to activate memory T cells in vitro. Thus, mRNA-transfected PBMCs are a convenient replacement of mRNA-transfected Mo-DCs for the in vitro monitoring of natural or vaccine-induced immune responses.Received 17 February 2005; received after revision 1 May 2005; accepted 7 Juni 2005     

Enhancement of humoral immune response against human lung elastin peptides

Summary When guinea pigs instead of rabbits were used as the host animals, 8–16 times higher antibody titers against human lung elastin peptides were produced with only 1/20 the amount of antigen per unit body weight. This corresponds to a 200-fold enhancement of the immune response.Presented at the 6th Colloquium of the Federation of European Connective Tissue Clubs, Paris, August 28–30, 1978. The data form part of the Ph.D. thesis submitted by T.V. Darnule to the Department of Biology, New York University. Supported in part by NIH Program Project Grant HL15832 and by a Parker B. Francis Fellowship to T.V. Darnule.     

Immune-mediated glomerulonephritis induced by mercuric chloride in mice

Summary The BALB/c mouse developed mesangial deposits of immune constituents and light microscopical changes characteristic of immune complex glomerulonephritis after 8 weeks' treatment with mercuric chloride given by s.c. injection. There were no signs of linear of granular immune deposits along the glomerular capillary basement membrane after 2 or 8 weeks. The antigen could not be identified. No antibodies to nuclear or renal structures were found. Using a histochemical method (silver amplification) mercury was detected by light and electron microscopy in tubular and glomerular structures. Mercury was present in secondary lysosomes of the mesangial cells after eight weeks of mercury poisoning.We are deeply indebted to Dr. Gorm Danscher, Institute of Anatomy, B., University of Aarhus, Denmark, for valuable discussions and technical advice. This work was supported by the Swedish Medical Research Council, project no 6536.     

Direct evidence that the N-terminal extensions of the TAP complex act as autonomous interaction scaffolds for the assembly of the MHC I peptide-loading complex

The loading of antigenic peptides onto major histocompatibility complex class I (MHC I) molecules is an essential step in the adaptive immune response against virally or malignantly transformed cells. The ER-resident peptide-loading complex (PLC) consists of the transporter associated with antigen processing (TAP1 and TAP2), assembled with the auxiliary factors tapasin and MHC I. Here, we demonstrated that the N-terminal extension of each TAP subunit represents an autonomous domain, named TMD(0), which is correctly targeted to and inserted into the ER membrane. In the absence of coreTAP, each TMD(0) recruits tapasin in a 1:1 stoichiometry. Although the TMD(0)s lack known ER retention/retrieval signals, they are localized to the ER membrane even in tapasin-deficient cells. We conclude that the TMD(0)s of TAP form autonomous interaction hubs linking antigen translocation into the ER with peptide loading onto MHC I, hence ensuring a major function in the integrity of the antigen-processing machinery.     

The effect of renal hydrodynamics on immune complex deposition

Summary The role of renal hydrodynamics on renal deposition of immune complexes was evaluated in acute serum sickness. Using i.v. radiolabelled antigen in rabbits under a variety of hydrodynamic alterations, these studies suggested that although intrarenal hydrodynamics influence renal deposition of immune complexes factors other than intrarenal hydrostatic pressure may be important.Supported by grants in aid from the Rocky Mountain Kidney Foundation, Colorado Heart Association, USPHS No. GRS 5 SO1 RR 05357 and USPHS No. HD 04024.Dr. Ozawa is a fellow in Neprhology.This work was performed during the tenure of an Established Investigatorship from the American Heart Association (Dr.McIntosh).     

An hypothesis for the process of selection at the subcellular level leading to the appearance of new clones]

According to the hypothesis we propose, the stimulation of one lymphocyte by an antigen induces the simultaneous expression of a great diversity of immunoglobulins of different specificities. Each molecular species is associated with the corresponding mRNA within a subcellular structure: the ergastoplasmic cisterna. It has been shown that in some responding lymphocytes at an early stage of the immune response a few such cisternae are loaded with antibodies while most of the cisternae are synthesizing non specific immunoglobulins. The main point of our proposal is that the selective action of antigen bears on these cisternae and that the mRNA corresponding to the immunoglobulins fitting best to the antigen is transcribed to DNA which is then inserted into the genome. This cell and its progeny become thereafter a monospecific clone submitted to regulation as an element of the network.     

Inhibition of SRC family kinases facilitates anti-CTLA4 immunotherapy in head and neck squamous cell carcinoma

The immune system plays a critical role in the establishment, development, and progression of head and neck squamous cell carcinoma (HNSCC). As treatment with single-immune checkpoint agent results in a lower response rate in patients, it is important to investigate new strategies to maintain favorable anti-tumor immune response. Herein, the combination immunotherapeutic value of CTLA4 blockade and SFKs inhibition was assessed in transgenic HNSCC mouse model. Our present work showed that tumor growth was not entirely controlled when HNSCC model mice were administered anti-CTLA4 chemotherapeutic treatment. Moreover, it was observed that Src family kinases (SFKs) were hyper-activated and lack of anti-tumor immune responses following anti-CTLA4 chemotherapeutic treatment. We hypothesized that activation of SFKs is a mechanism of anti-CTLA4 immunotherapy resistance. We, therefore, carried out combined drug therapy using anti-CTLA4 mAbs and an SFKs’ inhibitor, dasatinib. As expected, dasatinib and anti-CTLA4 synergistically inhibited tumor growth in Tgfbr1/Pten 2cKO mice. Furthermore, dasatinib and anti-CTLA4 combined to reduce the number of myeloid-derived suppressor cells and Tregs, increasing the CD8⁺ T cell-to-Tregs ratio. We also found that combining dasatinib with anti-CTLA4 therapy significantly attenuated the expression of p-STAT3^Y705 and Ki67 in tumoral environment. These results suggest that combination therapy with SFKs inhibitors may be a useful therapeutic approach to increase the efficacy of anti-CTLA4 immunotherapy in HNSCC.