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Semi-allogeneic vaccine for T-cell lymphoma
Jin Yu, Mark S Kindy, Sebastiano Gattoni-Celli
Journal of Translational Medicine , 2007, DOI: 10.1186/1479-5876-5-39
Abstract: Semi-allogeneic somatic cell hybrids were generated by the fusion of EL-4 T lymphoma cells (H-2b) and BALB/c-derived renal adenocarcinoma RAG cells (H-2d). Cell hybrids were injected intra-peritoneally (i.p.) in C57BL/6 mice (H-2b) before challenging the mice with a tumorigenic dose of EL-4 cells.Semi-allogeneic tumor cell hybrids could not form a tumor in the animal host because they expressed allogeneic determinants (H-2d) and were rejected as a transplant. However, they conferred protection against a tumorigenic challenge of EL-4 cells compared to control mice that were mock-vaccinated with i.p.-injected phosphate-buffered saline (PBS) and in which EL-4 lymphomas grew rapidly to a large size in the peritoneal cavity. Screening of spleen-derived RNA by means of focused microarray technology revealed up-regulation of genes involved in the Th-1-type immune response and in the activation of dendritic antigen-presenting cells (APC).The results of our studies are entirely consistent with the concept that CD80- and CD86-expressing APC play a central role in mediating the immune protection induced by semi-allogeneic vaccines by activating a Th-1 response and instructing T cells responsible for killing autologous tumor cells.The capacity of T cells to recognize allogeneic MHC molecules as intact structures on the surface of foreign cells is called direct T-cell allorecognition and is responsible for the powerful immune reactions associated with transplant rejection, a phenomenon called "alloagression". To a large extent this is due to the ability of allogeneic stimulation to mobilize up to 10% of all T lymphocytes, compared with a precursor T-cell frequency of between 10-4 and 10-5 for most common antigens. At the same time, each of the lymphocytes activated through direct allorecognition will also recognize a specific antigenic peptide presented in the context of a self major histocompatibility complex (MHC) molecule (MHC restriction). Cross-reactivity between alloantige
Innate and Adaptive Immune Interactions at the Fetal–Maternal Interface in Healthy Human Pregnancy and Pre-Eclampsia  [PDF]
Peter Hsu,Ralph Kay Heinrich Nanan
Frontiers in Immunology , 2014, DOI: 10.3389/fimmu.2014.00125
Abstract: Maternal immune tolerance of the fetus is indispensable for a healthy pregnancy outcome. Nowhere is this immune tolerance more important than at the fetal–maternal interface – the decidua, the site of implantation, and placentation. Indeed, many lines of evidence suggest an immunological origin to the common pregnancy-related disorder, pre-eclampsia. Within the innate immune system, decidual NK cells and antigen presenting cells (including dendritic cells and macrophages) make up a large proportion of the decidual leukocyte population, and are thought to modulate vascular remodeling and trophoblast invasion. On the other hand, within the adaptive immune system, Foxp3+ regulatory T cells are crucial for ensuring immune tolerance toward the semi-allogeneic fetus. Additionally, another population of CD4+HLA-G+ suppressor T cells has also been identified as a potential player in the maintenance of immune tolerance. More recently, studies are beginning to unravel the potential interactions between the innate and the adaptive immune system within the decidua, that are required to maintain a healthy pregnancy. In this review, we discuss the recent advances exploring the complex crosstalk between the innate and the adaptive immune system during human pregnancy.
Twisting immune responses for allogeneic stem cell therapy  [cached]
Shengwen Calvin Li,Jiang F Zhong
World Journal of Stem Cells , 2009,
Abstract: Stem cell-derived tissues and organs have the potential to change modern clinical science. However, rejection of allogeneic grafts by the host’ s immune system is an issue which needs to be addressed before embryonic stem cell-derived cells or tissues can be used as medicines. Mismatches in human leukocyte class I antigens and minor histocompatibility antigens are the central factors that are responsible for various graft-versus-host diseases. Traditional strategies usually involve suppressing the whole immune systems with drugs. There are many side effects associated with these methods. Here, we discuss an emerging strategy for manipulating the central immune tolerance by naturally “ introducing” donor antigens to a host so a recipient can acquire tolerance specifically to the donor cells or tissues. This strategy has two distinct stages. The first stage restores the thymic function of adult patients with sex steroid inhibitory drugs (LHRH-A), keratinocyte growth factor (KGF), interleukin 7 (IL-7) and FMS-like tyrosine kinase 3 (FLT3). The second stage introduces hematopoietic stem cells and their downstream progenitors to the restored thymus by direct injection. Hematopoietic stem cells are used to introduce donor antigens because they have priority access to the thymus. We also review several clinical cases to explain this new strategy.
The ability of natural tolerance to be applied to allogeneic tissue: determinants and limits
William FN Chan, Ainhoa Perez-Diez, Haide Razavy, Colin C Anderson
Biology Direct , 2007, DOI: 10.1186/1745-6150-2-10
Abstract: We found that internal transplants mismatched for a single minor-H antigen and 'healed-in' before immune system development were not ignored but instead induced natural tolerance. In contrast, multiple minor-H or MHC mismatched transplants did not consistently induce natural tolerance unless they carried chimerism generating passenger lymphocytes. To determine whether the systemic nature of passenger lymphocytes was required for their tolerizing capacity, we generated a model of localized vs. systemic donor lymphocytes. We identified the peritoneal cavity as a site that protects allogeneic lymphocytes from killing by NK cells, and found that systemic chimerism, but not chimerism restricted to the peritoneum, was capable of generating natural tolerance.These data provide an explanation for the variable results with pre-immunocompetence transplants and suggest that natural tolerance to transplants is governed by the systemic vs. localized nature of donor antigen, the site of transplantation, and the antigenic disparity. Furthermore, in the absence of systemic lymphocyte chimerism the capacity to establish natural tolerance to allogeneic tissue appears strikingly limited.This article was reviewed by Matthias von Herrath, Irun Cohen, and Wei-Ping Min (nominated by David Scott).Reviewed by Matthias von Herrath, Irun Cohen, and Wei-Ping Min (nominated by David Scott). For the full reviews, please go to the Reviewers' comments section.Transplantation of donor cells/tissues prior to the development of recipient immunocompetence theoretically provides the greatest opportunity to achieve donor specific tolerance (for our definition of key terms, such as tolerance, see Additional File 1). All of the tolerance processes that occur for self-reactive T cells are potentially available for donor reactive T cells, and in most cases the transplant has time to heal-in prior to encountering the recipient's immune system, potentially eliminating or reducing the APC activating signals fr
Co-Graft of Allogeneic Immune Regulatory Neural Stem Cells (NPC) and Pancreatic Islets Mediates Tolerance, while Inducing NPC-Derived Tumors in Mice  [PDF]
Raffaella Melzi,Barbara Antonioli,Alessia Mercalli,Manuela Battaglia,Andrea Valle,Stefano Pluchino,Rossella Galli,Valeria Sordi,Emanuele Bosi,Gianvito Martino,Ezio Bonifacio,Claudio Doglioni,Lorenzo Piemonti
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010357
Abstract: Data available on the immunomodulatory properties of neural stem/precursor cells (NPC) support their possible use as modulators for immune-mediated process. The aim of this study was to define whether NPC administered in combination with pancreatic islets prevents rejection in a fully mismatched allograft model.
Immune Modulation by Chemotherapy or Immunotherapy to Enhance Cancer Vaccines  [PDF]
Genevieve M. Weir,Robert S. Liwski,Marc Mansour
Cancers , 2011, DOI: 10.3390/cancers3033114
Abstract: Chemotherapy has been a mainstay in cancer treatment for many years. Despite some success, the cure rate with chemotherapy remains unsatisfactory in some types of cancers, and severe side effects from these treatments are a concern. Recently, understanding of the dynamic interplay between the tumor and immune system has led to the development of novel immunotherapies, including cancer vaccines. Cancer vaccines have many advantageous features, but their use has been hampered by poor immunogenicity. Many developments have increased their potency in pre-clinical models, but cancer vaccines continue to have a poor clinical track record. In part, this could be due to an inability to effectively overcome tumor-induced immune suppression. It had been generally assumed that immune-stimulatory cancer vaccines could not be used in combination with immunosuppressive chemotherapies, but recent evidence has challenged this dogma. Chemotherapies could be used to condition the immune system and tumor to create an environment where cancer vaccines have a better chance of success. Other types of immunotherapies could also be used to modulate the immune system. This review will discuss how immune modulation by chemotherapy or immunotherapy could be used to bolster the effects of cancer vaccines and discuss the advantages and disadvantages of these treatments.
Normal Human Pregnancy Results in Maternal Immune Activation in the Periphery and at the Uteroplacental Interface  [PDF]
Andrea I. Loewendorf, Tina A. Nguyen, Maria N. Yesayan, Daniel A. Kahn
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0096723
Abstract: Pregnancy poses a unique challenge to the human immune system: the semi-allogeneic fetus must be protected from maternal immune attack while immunity towards pathogens is maintained. Breakdown in maternal-fetal tolerance can lead to pregnancy-specific diseases with potentially high degrees of morbidity and mortality for both the mother and her fetus. Various immune cell-types could mediate these functions, but a comprehensive evaluation of the peripheral and local maternal T cell and regulatory T cell compartments in normal human pregnancy is lacking. In this case-control study, we apply the Human Immunology Project Consortium proposed gating strategies to samples from healthy 3rd trimester human subjects compared with healthy non-pregnant controls. The proportions of HLA-DR+ and CD38+ effector- and effector memory CD8 T cells are significantly increased in the peripheral blood of pregnant women. Utilizing a novel technique that takes advantage of the standard protocol for intrauterine cleanup after cesarean section, we isolate lymphocytes resident at the uteroplacental interface (UPI). At the UPI, the CD4 and CD8 T cell compartments largely mirror the peripheral blood, except that the proportion of HLA-DR+ activated T regulatory cells is significantly increased in direct proportion to an observed increase in the number of activated CD8 T cells. We find that cryopreservation and delayed sample processing (>12 hours) decreases our ability to identify regulatory T cell subsets. Further, the Consortium proposed method for Treg identification underrepresents Resting and Cytokine Tregs compared with Activated Tregs, thus skewing the entire population. Better understanding of the changes in the immune system during pregnancy in the peripheral blood and at the uteroplacental interface are essential for progress in treatment of pregnancy diseases such as pre-eclampsia and recurrent miscarriage.
Vaccines against Human Carcinomas: Strategies to Improve Antitumor Immune Responses
Claudia Palena,Jeffrey Schlom
Journal of Biomedicine and Biotechnology , 2010, DOI: 10.1155/2010/380697
Abstract: Multiple observations in preclinical and clinical studies support a role for the immune system in controlling tumor growth and progression. Various components of the innate and adaptive immune response are able to mediate tumor cell destruction; however, certain immune cell populations can also induce a protumor environment that favors tumor growth and the development of metastasis. Moreover, tumor cells themselves are equipped with various mechanisms that allow them to evade surveillance by the immune system. The goal of cancer vaccines is to induce a tumor-specific immune response that ultimately will reduce tumor burden by tipping the balance from a protumor to an antitumor immune environment. This review discusses common mechanisms that govern immune cell activation and tumor immune escape, and some of the current strategies employed in the field of cancer vaccines aimed at enhancing activation of tumor-specific T-cells with concurrent reduction of immunosuppression.
The Specificity of Targeted Vaccines for APC Surface Molecules Influences the Immune Response Phenotype  [PDF]
Gunnveig Gr?deland, Siri Mjaaland, Gro Tunheim, Agnete B. Fredriksen, Bjarne Bogen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080008
Abstract: Different diseases require different immune responses for efficient protection. Thus, prophylactic vaccines should prime the immune system for the particular type of response needed for protection against a given infectious agent. We have here tested fusion DNA vaccines which encode proteins that bivalently target influenza hemagglutinins (HA) to different surface molecules on antigen presenting cells (APC). We demonstrate that targeting to MHC class II molecules predominantly induced an antibody/Th2 response, whereas targeting to CCR1/3/5 predominantly induced a CD8+/Th1 T cell response. With respect to antibodies, the polarizing effect was even more pronounced upon intramuscular (i.m) delivery as compared to intradermal (i.d.) vaccination. Despite these differences in induced immune responses, both vaccines protected against a viral challenge with influenza H1N1. Substitution of HA with ovalbumin (OVA) demonstrated that polarization of immune responses, as a consequence of APC targeting specificity, could be extended to other antigens. Taken together, the results demonstrate that vaccination can be tailor-made to induce a particular phenotype of adaptive immune responses by specifically targeting different surface molecules on APCs.
Tolerance of the fetus by the maternal immune system: role of inflammatory mediators at the feto-maternal interface
Colette Kanellopoulos-Langevin, Stéphane M Caucheteux, Philippe Verbeke, David M Ojcius
Reproductive Biology and Endocrinology , 2003, DOI: 10.1186/1477-7827-1-121
Abstract: Placental mammals have been subjected to two opposing selective pressures during evolution, as survival of the species depends on the ability to eliminate microbial pathogens while at the same time protecting fetuses from immune rejection. In this respect, it is noteworthy that placentation had to evolve in animals that already possessed a major histocompatibility complex (MHC). One could therefore speculate that the innate immune system at the feto-maternal interface underwent less stringent selective pressures to ensure quick and efficient local protection against infection, while the adaptive immune system had to remain under full control to prevent rejection of the semi-allogeneic fetus. Given the high selective pressures at work, pregnancy failures unequivocally related to immune dysregulation are therefore rare events, whether in the human species or laboratory animals. Conversely, there are many examples of abortion or fetal distress due to placental inflammation and/or infection.A number of excellent reviews have been published recently on adaptive immune responses during pregnancy [1-6]. The local activation of some components of the innate immune system at the feto-maternal interface is attracting a growing interest from the reproductive immunology community. This review will emphasize aspects of the innate immune system that could contribute to reproductive failure.Apoptosis can be triggered by the Th1 cytokine, TNFα, or the Fas ligand (Fas-L). As human syncytiotrophoblasts and cytotrophoblasts in placental villi and chorionic extravillous trophoblasts produce the Fas-L, it has been proposed that trophoblast Fas-L may contribute to placental immune privilege during pregnancy by promoting apoptosis of activated, Fas-bearing maternal lymphocytes at the feto-maternal interface (Fig. 1). This view is supported by studies with isolated human peripheral blood lymphocytes co-cultured with trophoblasts [7], but the data are less clear in animal models. The lpr mu
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