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Thirteen acylated and phosphorylated derivatives of beta-1,6-linked glucosamine disaccharide (lipid A analogs), which were synthesized after the structural model of Salmonella-type lipid A, and seven similar derivatives of glucosamine monosaccharide (lipid A-related compounds) were studied for their immunobiological activities. These included mitogenicity and polyclonal B cell activation enhancement of migration of monocytes and polymorphonuclear leukocytes derived from human peripheral blood, stimulation of guinea pig peritoneal macrophages, activation of human complement, and stimulation of serum antibody production and induction of delayed-type hypersensitivity against ovalbumin in guinea pigs. Comparisons were made with lipid A, RE-glycolipid, lipopolysaccharide of natural sources, and a well-known synthetic adjuvant, N-acetylmuramyl-L-alanyl-D-isoglutamine. Some of the lipid A analogs were found to manifest the mitogenic, polyclonal B cell-activating macrophage-stimulating, complement-activating, and immunostimulating activities, although the observed activities were generally far less than those of natural products in intensity and efficiency. Other immunobiological effects exhibited by most of the synthetic lipid A analogs were the enhancement of migration of monocytes and polymorphonuclear leukocytes. It is premature to draw definite conclusions on structure-activity relationships, since a few compounds which were active in some assay systems were scarcely active in other assays. However, an indisputable fact was that beta-1,6-glucosamine disaccharide 1 alpha,4'-diphosphate, which carries two amide-bound (R)-3-hydroxytetradecanoyl and three ester-bound tetradecanoyl residues, and thus has the structure most closely resembling natural lipid A among test compounds in this study, was definitely active in all of the present assay systems. However, its potency was generally much less than natural products. Some of glucosamine monosaccharide derivatives, especially N-(R)-3-[(R)-3-hydroxytetradecanoyloxy]tetradecanoyl glucosamine, also exerted all of the in vitro activities described above. This fact suggests that a glucosamine disaccharide structure may not necessarily be a prerequisite as far as the in vitro immunobiological activities tested are concerned.
Lipoteichoic acid (LTA) derived from Staphylococcus aureus is reported to be a ligand of TLR2. However, we previously demonstrated that LTA fraction prepared from bacterial cells contains lipoproteins, which activate cells via TLR2. In this study, we investigated the immunobiological activity of LTA fraction obtained from S. aureus wild-type strain, lipoprotein diacylglycerol transferase deletion (delta lgt) mutant, which lacks palmitate-labeled lipoproteins, and its complemented strain and evaluated the activity of LTA molecule. LTA fraction was prepared by butanol extraction of the bacteria followed by hydrophobic interaction chromatography. Although all LTA fractions activated cells through TLR2, the LTA from delta lgt mutant was 100-fold less potent than those of wild-type and complemented strains. However, no significant structural difference in LTA was observed in NMR spectra. Further, alanylation of LTA molecule showed no effect in immunobiological activity. These results showed that not LTA molecule but lipoproteins are dominant immunobiologically active TLR2 ligand in S. aureus.
To better understand the immunobiology of dendritic cells (DCs), we took the expressed sequence tag (EST) approach to describe their transcript profile and discovered novel genes. ESTs (n = 25,668) were generated from monocyte-derived DCs, and 15,863 ESTs (61.8%) represented unique genes in GenBank. Integration of ESTs allowed for the generation of a profile of 4,367 known genes and identification of > 100 novel genes. HLA-DR invariant chain p33, cathepsin D, HLA-DR alpha chain, beta2-microglobulin, HLA-DP beta chain, CD11a, and mannose receptor were in the top 30 transcripts, and 451 known genes were potentially associated with the immunobiology of DCs. This transcript profile was consistent with the unique antigen-presenting capacity of DCs and provided invaluable information to better understand the immunobiology of DCs. On the basis of the EST database, a full-length novel gene was identified that exhibited close homology with CD84; it was designated CD84-H1. The full-length cDNA of CD84-H1 contained an open reading frame of 870 bp encoding a type I transmembrane protein of 289 amino acids. Consistent with the structural feature of the CD2 family, the predicted 270-amino acid mature protein of CD84-H1 contained two extracellular immunoglobulin-like domains that shared homology with CD2 family members, e.g., CD84, Ly-9, CD48, and signaling lymphocyte activation molecule. Its intracellular domain was short and contained no putative signaling structure. Northern blot analysis revealed that CD84-H1 expression was predominantly restricted in hematopoietic tissues. Reverse transcription-PCR analysis showed that it was widely expressed in the immune cells, including monocytes, DCs, B cells, and T cells. These data indicate that CD84-H1 may be relevant to immune responses.
Heart transplantation has been performed clinically for four decades, and has become the standard of care for end-stage heart disease. Our understanding of the immunobiology of transplantation has made tremendous strides, but our knowledge still lags behind the clinical use. As a result, nonspecific immunosuppression remains the standard therapy. This chapter is a review of our present knowledge of the immunobiology of allotransplantation and xenotransplantation with emphasis on antigen presentation, costimulation, and T-cell activation in the context of transplantation. The molecular events of T-cell activation, with some emphasis on the sites of action of present day immunosuppression, are reviewed. Basic aspects of immunosuppression are reviewed elsewhere in this edition. Given the paucity of allografts, xenografts are being considered as an alternative donor source. This being the case, cellular and humoral response to xenografts is considered and contrasted with our understanding of allograft immunity. Basic mechanisms of tolerance are discussed, with examples of experimental tolerance induction in small and large animals. A brief description of special considerations for the immunology in human neonate/infant recipients is mentioned. Understanding the immunobiology of transplantation is key to making decisions regarding heart transplant recipients today, in addition to developing better protocols and the induction of tolerance in the future.
Immunobiologicals (vaccines, immunoglobulins and -sera) are considered to be the most cost-effective tools in the prevention of infectious diseases. Their importance will further increase due to various eradication programmes of the WHO and EU and the emergence of new infectious diseases or the re-emergence of diseases as diphtheria and tuberculosis. The production and quality control of immunobiologicals are regulated by monographs and guidelines, which are issued by international or national Pharmacopoeias (e.g. Ph. Eur.), international organisations (e.g. WHO, O.I.E.) and international regulatory bodies (e.g. EMEA). Their purpose is to assure the quality of the product, i.e. its safety and potency. It is estimated that 10 millions of laboratory animals are world-wide used for the production and quality control of immunobiologicals, of which 80% are needed for the safety and potency testing of the finished product (batch control). In recent decades, the use of Three Rs principles has been recognised by the above mentioned organisations and various national competent authorities and been incorporated into general monographs and guidelines. Several tests with questionable relevance have been deleted from Ph. Eur. monographs (e.g. abnormal toxicity test, extraneous agents testing of viral vaccines for carnivores) or are now carried out during production. Reduction of the number of animals used could be achieved by introducing single-dilution tests. A large number of immunochemical tests have been developed, which could completely or partly replace the use of animals for potency testing, however, only a few have been validated so far (e.g. ToBI and ELISA for potency testing of human and veterinary tetanus vaccine; ELISA for potency testing of erysipelas vaccine). Regulatory acceptance of validated alternative methods is still a critical step. In particular, the period between successful validation and the implementation appears to be far too long. Reasons for this could be the slow process of multinational agreement to revise pharmacopoeial monographs and guidelines, and the time-consuming and expensive production of sufficient reference material (antigen, sera etc) for the new test systems. The shift in the quality control concept from reliance on final batch testing to the concept of consistency of production offers the opportunity to reduce the numbers of animals being used and promote the use of alternative methods. Emphasis is put on a combination of in vitro tests, which could make it possible to monitor batch-to-batch consistency. This new concept of quality control is already in place for the new well-defined vaccines. In most cases, non-animal methods are used for monitoring consistency at critical steps in the production and testing of a vaccine. Whether the concept of consistency of production could be also applied to the conventional, less-defined products, should be investigated. Only little progress has been achieved with regard to international harmonisation. Most of the manufacturers produce for the world market, so harmonisation of the requirements or mutual recognition of tests would help to reduce the use of animals. There is agreement that for the time being animals will still be needed for the development of vaccines in order to gain best knowledge on the disease, the pathogen and the specific immune response, including: pathogenesis, identification of the protective antigens, the way the antigen is processed, the dynamics of the immune response, the induction of memory, and the selection of the best adjuvant. With regard to routine batch release of conventional products, a number of Three Rs approaches are already available and should further be developed and validated. Whereas routine batch release of new products should be based on in vitro methods already established during their development.
Antimicrobial peptides are ancient components of the innate immune system and have been isolated from organisms spanning the phylogenetic spectrum. Over an evolutionary time span, these peptides have retained potency, in the face of highly mutable target microorganisms. This fact suggests important coevolutionary influences in the host-pathogen relationship. Despite their diverse origins, the majority of antimicrobial peptides have common biophysical parameters that are likely essential for activity, including small size, cationicity, and amphipathicity. Although more than 900 different antimicrobial peptides have been characterized, most can be grouped as belonging to one of three structural classes: (1) linear, often of alpha-helical propensity; (2) cysteine stabilized, most commonly conforming to beta-sheet structure; and (3) those with one or more predominant amino acid residues, but variable in structure. Interestingly, these biophysical and structural features are retained in ribosomally as well as nonribosomally synthesized peptides. Therefore, it appears that a relatively limited set of physicochemical features is required for antimicrobial peptide efficacy against a broad spectrum of microbial pathogens. During the past several years, a number of themes have emerged within the field of antimicrobial peptide immunobiology. One developing area expands upon known microbicidal mechanisms of antimicrobial peptides to include targets beyond the plasma membrane. Examples include antimicrobial peptide activity involving structures such as extracellular polysaccharide and cell wall components, as well as the identification of an increasing number of intracellular targets. Additional areas of interest include an expanding recognition of antimicrobial peptide multifunctionality, and the identification of large antimicrobial proteins, and antimicrobial peptide or protein fragments derived thereof. The following discussion highlights such recent developments in antimicrobial peptide immunobiology, with an emphasis on the biophysical aspects of host-defense polypeptide action and mechanisms of microbial resistance.
Traditional investigations of hepatic dendritic cells (DC) have focused on immunohistochemical studies of these cells within normal and pathological liver tissue. The recent availability of reagents for the improved characterization of DC, together with cytokine-based methods for the expansion of liver DC both in vivo and in vitro have begun to provide new insight into the immunobiology of these important antigen-presenting cells. Hepatic DC probably play a key role in the host response to blood-borne pathogens, and in the pathogenesis of infectious and autoimmune liver diseases. They appear to be important in determining the balance between liver transplant tolerance and rejection. Their possible role in oral and portal venous tolerance remains to be defined. In this article, we focus on emerging aspects of hepatic DC immunobiology, with particular reference to liver transplantation.
Recent advances in cutaneous immunobiology have led to the realization that skin is an important and unique immunologic organ. Studies on the immunobiology of skin cancers induced by ultraviolet radiation indicate that immune mechanisms can play a crucial role in the development of cutaneous tumors. This paper summarizes the evidence linking skin and the immune system and discusses current hypotheses concerning the mechanisms by which UV radiation interferes with cutaneous immunity. The significance of these findings for cutaneous carcinogenesis is discussed.
The ability to maintain and study human tissues in an in vivo environment has proved to be a valuable tool in breast cancer research for several decades. The most widely studied tissues have been xenografts of established human breast cancer cell lines into athymic nude mice. Human breast tumor xenografts provide the opportunity to study various important interactions between the tumor and host tissues, including endocrinologic, immunologic, and tumor-stroma interactions. The nude mouse is not the only immune-deficient recipient system in which to study xenografts. Additional single and combined mutant strains have been used successfully, including mice homozygous for the severe combined immune deficiency mutation (scid), both the beige (bg) and nude (nu) mutations in combination (bg/nu), and mice bearing the combined bg/nu/xid mutations. The differing immunobiologies are discussed, with particular reference to the immunobiology of breast cancer, as are the characteristics of several of the more frequently utilized breast cancer xenografts and cell lines. The ability of several endocrine treatments to modulate effectors of cell mediated immunity, e.g., estrogens and antiestrogens, and the effect of site of inoculation on tumor take and metastasis, also are described.
Preliminary findings in the evaluation of the immune response of children with primary neoplasms of the CNS, mainly medulloblastomas, are reported and discussed. A broad scheme for the monitoring of B- and T-cell-dependent immunity and of delayed hypersensitivity reactions in this type of patient is presented. The most important immunobiological findings are discussed. Special attention is given to the striking failure of the T-cell-dependent pool (currently identified by "active" RFC and blastigenesis tests) and to the remarkable decrease of hypersensitivity reactions (depressed skin-test response), both of which seem to be related to the degree of malignancy of the tumour. A very peculiar feature, i.e., the appearance of cells with natural cytotoxic activity, is dealt with in some detail. Our present knowledge concerning the immunobiology of primary CNS neoplasms is still very incomplete, but seems to suggest a possible role for immunotherapy in paediatric neurosurgery.
The advent of technologies such as real-time reverse transcriptase polymerase chain reaction (RT-PCR) and cDNA microarrays herald a new era in the study of biological systems. In immunobiology, these advances have begun to impact studies of infectious diseases, inflammatory processes, and immune cell function. However, a lack of genetic reagents for domestic and companion animals has precluded widespread application of new technologies to studies in these systems. We have recently described development of cDNA microarrays for studying bovine immunobiology. Although powerful in revealing genes involved in immunological phenomena in cattle, these resources were limited by a lack of genes known to function in immune responses from other species, such as mouse and human. To address this shortcoming, we used a combination of bioinformatics and high throughput RT-PCR to create amplicons representing over 270 bovine genes whose orthologs in other species were known to function in immune responses. Amplified gene segments were prepared from cDNA representing RNA isolated from either unstimulated or concanavalin A (ConA) stimulated peripheral blood mononuclear cells (PBMCs). In total, 276 genes were amplified from cDNA representing unstimulated bovine PBMC RNA or from cDNA representing ConA stimulated bovine PBMC RNA. A web-accessible resource (http://gowhite.ans.msu.edu/public_php/gd-bovine-immunology.php) has been created to assist in dissemination of this novel resource. The web-accessible resource contains information on gene name, the forward and reverse primers used to amplify each segment, expected product size, and if the gene was found in unstimulated PBMCs or only in ConA stimulated PBMCs. Gene names appear as hyperlinks to the Genbank pages representing the bovine gene or expressed sequence tag (EST) used to generate each primer pair.
The use of mobilized peripheral blood (PB) stem cells for autologous transplantation initially generated much enthusiasm because of enhanced engraftment in comparison to marrow stem cells and avoidance of general anesthesia for the donor. Its application to the allogeneic setting seemed inevitable. For obvious ethical reasons, allogeneic donors are mobilized with cytokines only, mainly granulocyte colony-stimulating factor (G-CSF). Results from preliminary studies suggest that in comparison to standard bone marrow transplants, outcomes such as engraftment, host-versus-graft reaction, graft-versus-host disease, graft-versus-leukemia and immunological reconstitution may be different. Surprisingly, G-CSF, previously recognized as a late acting lineage-specific factor for neutrophil production, not only disrupts homeostasis between stem cells and their microenvironment, but also induces significant quantitative and qualitative changes in the accessory cell compartment, affecting lymphocytes, monocytes, natural killer, dendritic, and stromal cells. Furthermore, mobilization of huge numbers of non-professional antigen presenting cells (CD34+ stem cells) amplifies the tolerizing potential of PB stem cell grafts. Thus, G-CSF mobilization provides PB transplants with different immunobiologic properties in comparison to standard bone marrow grafts. Whether these immunobiologic differences will lead to better transplant outcomes remains to be shown through much awaited results of large randomized clinical trials.
The aim of the study was to determine the usefulness of new immunobiological tests using fractioned human inner ear antigen in the investigation of 4 Menière's disease and 12 rapidly progressive sensorineural hearing loss (RPSNHL). Each patient underwent a full ENT examination and a full range of immunobiological tests comprising ESR, electrophoresis, IgG, A, M, circulating immune complexes, cryoglobulins, complement, organ and non-organ auto-antibodies. The two new tests were the lymphocyte transformation test (LTT) and the immunoperoxidase test against total or fractioned human inner ear antigens. Four main bands were found in electrophoresis with the following molecular weights: 130,000, 45,000, 22,000, and 14,000. The heaviest band corresponded to IgG contained in the inner ear extract. Three cases of bilateral RPSNHL had positive LTT against inner ear antigens. No serum of patients showed a characteristics band with the immunoperoxidase test with regard to the serum of healthy subjects. At least four abnormal inflammatory non-specific tests were shown in the cases of positive LTT. Out of 3, 2 patients received steroids and improved their hearing.
Canine transmissible venereal tumour (CTVT) is the only known naturally occurring tumour that can be transplanted as an allograft across major histocompatibility (MHC) barriers within the same species, and even to other members of the canine family, such as foxes, coyotes and wolves. The progression of this tumour is unique in that, it follows a predictable growth pattern. In natural and experimental cases, the growth pattern includes progressive growth phase, static phase and regression phase, and this is followed by transplantation immunity in immunocompetent adults, while metastasis occurs in puppies and immunosuppressed dogs. Because of the uniqueness of CTVT transmission and progression, experimental investigations of various aspects of the biology of CTVT have been used to provide clues to the immunobiology of both animal and human tumours. This review examines the current state of knowledge of the aspects of the cytogenetic origin, immunophenotype, immunobiology and immunotherapy of CTVT.
Gestational trophoblastic diseases (GTDs) comprise a group of interrelated diseases characterized by development after gestation, widespread metastases, and high curability with chemotherapy. The good prognosis of GTDs is considered partly a result of the host immune response to paternal antigens expressed on trophoblastic cells. In this study, we review current understanding of the immunobiology of GTDs. First of all, we describe the microenvironment between trophoblastic cells and subpopulation of immune cells. Second, immunogenetics, immune microenvironment around abnormal trophoblast, and mechanism of GTDs escaping from maternal immune system surveillance were also discussed. Third, we propose the possible immunotherapy for persistent GTDs, particularly the vaccine designed on human chorionic gonadotrophin, which is generally accepted as a tumor marker for GTDs diagnosis. Due to the low incidence of GTDs and high response to chemotherapy, there have been few literatures about immunobiologic characteristics of GTDs compared with the other gynecologic malignancies, such as ovarian cancer, but the immunologic behavior of GTDs should be explored for further understanding of the etiology of these diseases and to help designing immunotherapeutic strategies for persistent GTDs.
Allogeneic hematopoietic stem cell transplantation (HSCT) has evolved into an effective adoptive cellular immunotherapy for the treatment of a number of cancers. The immunobiology of allogeneic HSCT is unique in transplantation in that it involves potential immune recognition and attack between both donor and host. Much of the immunobiology of allogeneic HSCT has been gleaned from preclinical models and correlation with clinical observations. We review our current understanding of some of the issues that affect the success of this therapy, including host-versus-graft (HVG) reactions, graft-versus-host disease (GVHD), graft-versus-tumor (GVT) activity, and restoration of functional immunity to prevent transplant-related opportunistic infections. We also review new strategies to optimize the GVT and improve overall immune function while reducing GVHD and graft rejection.
The CDC provides to the medical profession various drugs and immunobiological materials, many of which are investigational. The products available at CDC have changed over the years to meet the changing needs of the American public. Availability of the investigational drugs and immunobiologics permits treatment of patients with diseases against which no FDA-approved drug or treatment is effective and permits research and development of new drugs by manufacturers.