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At least 397 records · Page 22Linked to original sources
PubMed2002

Molecular recognition in antibody-antigen complexes.

With the numerous detailed molecular descriptions of antibody-antigen interfaces, the structual study of these molecular interactions has evolved from an attempt to understand to immunological function to their use as model systems for protein-protein interactions. In this chapter, we describe the structual aspects common to antibody-antigen interfaces and discuss the roles they may play in antibody cross-rectivity and molecular mimicry. More detailed analysis of these interfaces has required the marriage of structural studies with extensive mutagenesis and thermodynamic analysis efforts. Here, we discuss the thermodynamic mapping of interfaces for two model antibody-antigen complexes, including the identification of thermodynamic hot spots in binding and the various mechanism used to accommodate interface mutations. We also discuss the functional roles for protein plasticity in antigen recognition, including the entropic control of antibody affinity maturation and the use of induced fit mechanism of different types and to varying degrees by mature antibodies in binding their specific antigens.

Animals↗
PubMed1999

Animal models for gastric Helicobacter immunology and vaccine studies.

Over the last decade animal models have been used extensively to investigate disease processes and therapy for Helicobacter pylori infections. The H. pylori animal models which have been used in pathogenesis and vaccine studies include the gnotobiotic pig, non-human primates, cats, dogs, and several species of rodents including mice, rats, gerbils and guinea pigs. H. felis infection of mice and H. mustelae infection of ferrets have also been used. Recently, investigators have begun using transgenic mice and gene-targeted 'knock-out' mice to investigate Helicobacter infections. Each of these animal models has distinct advantages and disadvantages which are discussed in this minireview. The choice of an animal model is dictated by factors such as cost and an understanding of how each model will or will not allow fulfillment of experimental objectives.

Animals↗
PubMed2005

Immunologic pathways in a quantitative model of immunosuppression based on rejection of an allogeneic or xenogeneic tumor graft.

BACKGROUND: A quantitative model of immunosuppression was previously developed based on the rejection of the allogeneic A/J murine tumor sarcoma 1 (Sa1) in immunocompetent mice. Here, the model is used to evaluate the immunologic mechanisms of graft rejection and to determine the potential of this model to detect synergistic effects of combined immunosuppressive therapies. METHODS: Wild-type, genetically-deficient, or drug-treated mice were used. Mice were challenged subcutaneously with the allogeneic murine tumor cell line, Sa1, or with the xenogenic human tumor, MDA435. Tumor growth was monitored with time, with increasing tumor size reflecting greater immunosuppression. In some cases, the mice were presensitized with either Sa1 or with A/J splenocytes. RESULTS: In naïve recipient mice, studies in major histocompatibility complex (MHC)-I-deficient mice and with depleting anti-CD8 monoclonal antibody (mAb) demonstrate that CD8 T cells are important for Sa1 rejection. A modest role for perforin but not for Fas/Fas ligand could be demonstrated. Blockade of CD4 T cells was more effective with decreasing histocompatibility barriers. In contrast, CD4 T cells were critical in second-set rejections, but CD8 T cells were not. Rejection of xenogeneic tumors was also T-cell dependent as demonstrated by anti-CD3 mAb, dependent on both CD4 and CD8 T cells as demonstrated using MHC-I- and MHC-II-deficient mice, but was more vigorous as demonstrated by the lack of effectiveness of immunosuppressive drugs in this model. CONCLUSIONS: This model can be used to define dominant and partial effects of immunologic pathways as well as synergistic interactions of agents to develop immunosuppressive strategies.

Animals↗
PubMed1975

An experimental model for evaluation of factors in tumor escape from immunological attack.

A model system is presented for studying the factors involved in tumor immunity. The initial observations with this system concern the importance of dose and route of administration of tumor cells on tumor growth. The data show that myeloma tumor cells, when inoculated i.v.in relatively large numbers, are eradicated by the immune response of an allogeneic host; tumor cells administered i.v. in smaller number escape from immune attack even though the host has the potential to mount an immune response. BALB/c mouse myeloma cells (MOPC-21) were transplanted s.c., i.p., or i.v. into H-2-compatible allogeneic DBA/ 2 mice. There was a marked difference in the response of the host to tumor given s.c. or i.p. as compared to tumor given i.v. Thus s.c. or i.p. inoculation resulted in lethal tumor growth when 5 x 10-3 or more tumor cells were given. In contrast, the outcome of i.v. inoculation depended on tumor cell dose. Although small cell doses ( 5x 10-4 down to 10-2) resulted in lethal tumor gosulted in lethal tumor growth with only 10% survival, large cell doses (10-5 to 5 x 10-7) resulted in tumor rejection and 70% survival. DBA/2 mice possess the immunological ability to react agaist the tumor when large doses of tumor cells (10-7) are given i.v. or i.p., since spleen cells obtained from such mice were found to be able to suppress the growth of MOPC-21 when a mixture of spleen cells and tumor cells was inoculated. On the basis of these initial observations, our model appears to relate especially to the idea that, in autochithonous tumor development or in metastasis of tumor, a small number of antigenic tumor cells, perhaps even a single cell, usually grows into a frank tumor in spite of the immunological competence od the host to respond to the tumor cells.

Animals↗
PubMed1994

The Rhesus monkey as a model for testing the immunological effects of space flight.

The Rhesus monkey has been proposed as a model for the effects of space flight on immunity. In order to determine the feasibility of the use of the Rhesus monkey as a model, we studied the use of Rhesus monkey cells for immunological procedures that have been shown to be affected by space flight in both rodents and humans. We have shown that both lymph node cells and peripheral blood leukocytes can be stained with monoclonal antibodies to detect the following surface markers: CD4, CD-8, Ia and surface immunoglobulin. Also, the level of Ia antigen expression was increased by treatment of the cells with human interferon-gamma. In addition, cells were induced to produce interferons and interleukins. Isolated neutrophils also demonstrated increased oxidative burst. These data indicate that the Rhesus monkey will be a useful model for space flight studies of immunity.

Animals↗
PubMed2005

Severe combined immunodeficiency. A model disease for molecular immunology and therapy.

Severe combined immunodeficiencies (SCIDs) consist of genetically determined arrest of T-cell differentiation. Ten different molecular defects have now been identified, which all lead to early death in the absence of therapy. Transplantation of allogeneic hematopoietic stem cells (HSCT) can restore T-cell development, thus saving the lives of SCID patients. In this review, the different characteristics of HSCT are discussed along with the available data regarding the long-term outcome. Transient thymopoiesis caused by an exhaustion of donor progenitor cells and possibly a progressive loss of thymus function can lead to a progressive decline in T-cell functions. The preliminary results of gene therapy show the correction of two SCID conditions. Based on the assumption that long-lasting pluripotent progenitor cells are transduced, these data suggest that gene therapy could overcome the long-term recurrence of the T-cell immunodeficiency. SCID is thus a disease model for experimental therapy in the hematopoietic system.

Genetic Therapy↗
PubMed1996

Phosphodiesterase inhibitors correct resistance to natriuretic peptides in rats with Heymann Nephritis.

Experimental nephrotic syndrome is characterized by abnormal sodium metabolism, reflected in a blunted natriuretic response both to volume expansion and to infused atrial natriuretic peptide (ANP). The studies presented here examined the relationships among plasma ANP concentration and urinary sodium (VNaV) and cyclic GMP excretion (UcGMPV) in vivo, and the responsiveness of isolated glomeruil and inner medullary collecting duct (IMCD) cells to ANP and urodilatin (renal natriuretic peptide; RNP) in vitro in rats with Heymann nephritis, an immunologically mediated model of nephrotic syndrome. Nine to 14 days after Ip injection of anti-Fx1A antiserum, rats were proteinuric and had a blunted natriuretic response to intravenous infusion of isotonic saline (2% body weight, given over 5 min). Thirty min after the onset of the infusion, plasma ANP concentration was increased to the same extent in both normal and nephritic rats, compared with their respective hydropenic controls. Despite this increase, UcGMPV was significantly less in nephritic rats after the saline infusion. Accumulation of cGMP by isolated glomeruil and IMCD cells from nephritic rats after incubation with ANP and RNP was also significantly reduced, compared with normal rats. This difference was not related to differences in either density or affinity of renal ANP receptors, but was abolished when accumulation of cGMP was measured in the presence of 10(-3) M isobutylmethylxanthine or Zaprinast, two different inhibitors of cyclic nucleotide phosphodiesterases (PDE). Infusion of Zaprinast into one renal artery in nephritic rats normalized both the natriuretic response to volume expansion and the increase in UcGMPV from the infused, but not the contralateral, kidney. Furthermore, cGMP-PDE activity was increased in IMCD cell homogenates from nephritic compared with normal rats (388 +/- 32 versus 198 +/- 93 pmol/min per mg protein, P < 0.03). These results indicate that blunted volume expansion natriuresis accompanied by cellular resistance to ANP in vitro occurs in an immunologic model of renal injury. The resistance is not related to an alteration in ANP release or binding to its renal receptors, but is suppressed by PDE inhibitors and is associated with increased renal cGMP. PDE activity, thus suggesting that enhanced cGMP-PDE activity may account for resistance to the natriuretic actions of ANP observed in vivo. This defect may represent the intrinsic sodium transport abnormality linked to sodium retention in nephrotic syndrome.

1-Methyl-3-isobutylxanthine↗
PubMed2002

Comparative study of the high molecular mass fraction and low molecular mass fraction of Sho-saiko-to in a murine immunologically induced liver injury model.

We compared the pharmacological actions of the high and low molecular mass fractions of Sho-saiko-to using a murine immunologically induced liver injury model to estimate the roles of these fractions in the expression of the pharmacological action. In a Bacillus Calmette-Guerin (BCG)/lipopolysaccharide (LPS)-induced liver injury model, Sho-saiko-to and both of its fractions significantly reduced the increases in the aminotranseferase levels in serum. They also reduced the increase in the nitric oxide (NOx) level in serum. On the other hand, Sho-saiko-to and its high molecular mass fraction suppressed the increase in plasma NOx level in an LPS-induced endotoxin shock model but its low molecular mass fraction did not. These results suggest the possibility that both fractions act hepatoprotectively in a different manner. We believe that these results can help to elucidate the mechanism of action of ingredients in Sho-saiko-to.

Animals↗
PubMedDate not supplied

Cell-mediated cytotoxicity in recovery from poxvirus infections.

The availability of mutant and gene targeted knockout mice with defects in components of cellular cytotoxicity mediated by either the Fas or the exocytosis pathway permitted an analysis of their role in recovery from poxvirus infections. Ectromelia (EV), a natural mouse pathogen causing mousepox, the closely related orthopoxviruses cow pox (CPV) and vaccinia virus (VV), each encode serpins that inhibit Fas mediated apoptosis and lysis of target cells. Nevertheless, distinct differences were seen when the three viruses were inoculated into perforin-deficient mice: highly resistant C57Bl/6 mice became susceptible to low doses of EV; resistance to CPV increased whereas there was no effect on VV infections. Absence of the cytolytic granule associated granzymes (gzm) A and B rendered C57Bl/6 mice increasingly more susceptible to EV infections. Lack of both gzms rendered them as susceptible as perforin deficient mice, despite the presence of functionally active perforin. Elevated EV titres in liver and spleen of gzmA x B deficient mice, early after infection and before cytotoxic T cells were detectable, strongly suggests that these two gzms exert an antiviral effect by a mechanism distinct from effector molecules of NK and cytotoxic T cells.

Animals↗
PubMed2006

Immune selective pressure and HLA class I antigen defects in malignant lesions.

The revived cancer immune surveillance theory has emphasized the active role the immune system plays in eliminating tumor cells and in facilitating the emergence of their immunoresistant variants. MHC class I molecule abnormalities represent, at least in part, the molecular phenotype of these escape variants, given the crucial role of MHC class I molecules in eliciting tumor antigen-specific T cell responses, the high frequency of HLA class I antigen abnormalities in malignant lesions and their association with a poor clinical course of the disease. Here, we present evidence for this possibility and review the potential mechanisms by which T cell selective pressure participates in the generation of tumor cells with MHC class I molecule defects. Furthermore, we discuss the strategies to counteract tumor cell immune evasion.

Animals↗
PubMed1995

Morphostasis and immunity.

Scientists have traditionally been resistant to fundamental changes in perspective. New ideas are rejected if they challenge essential, accepted paradigms. Here I present a concept that, I believe, represents a paradigm shift in the way self/non-self discrimination is perceived. Traditional opinion has it that lymphocytes carry out this discrimination. I propose an alternative view. Self/non-self discrimination is driven by mechanisms closely related to those that lead to cell sorting in disaggregated embryos. Lymphocytes are only used to classify cells according to their mode of death (apoptosis or necrosis). The hypothesis outlines the process of morphostasis (tissue homeostasis). It fills in much detail about the gradual evolution of the mammalian immune system. Earlier versions of this hypothesis have been reflexly rejected by numerous journals. Until recently, I too was unsure of the validity of the core concept. Recent publications have dispelled this doubt from my mind. A paradigm shift is due.

Animals↗
PubMed2006

Reshaping the past: Strategies for modulating T-cell memory immune responses.

Memory T cells are generated following an initial encounter with antigen, persist over the lifetime of an individual, and mediate rapid and robust functional responses upon antigenic recall. While immune memory is generally associated with protective immune response to pathogens, memory T cells can be generated to diverse types of antigens including autoantigens and alloantigens through homologous or crossreactive priming and comprise the majority of circulating T cells during adulthood. Memory T cells can therefore play critical roles in propagating and perpetuating autoimmune disease and in mediating allograft rejection, although the precise pathways for regulation of memory immune responses remain largely undefined. Moreover, evaluating and designing strategies to modulate memory T-cell responses are challenging given the remarkable heterogeneity of memory T cells, with different subsets predominating in lymphoid versus non-lymphoid tissue sites. In this review, we discuss what is presently known regarding the effect of current immunomodulation strategies on the memory T-cell compartment and potential strategies for controlling immunological recall.

Animals↗
PubMed2006

Differentiation of memory B and T cells.

In the past few years progress has been made in understanding the molecular mechanisms that underlie the initial generation, and the ensuing differentiation and maintenance, of humoral and cellular immunity. Although B and T cell immunological memory contribute to protective immunity through fundamentally distinct effector functions, interesting analogies are becoming apparent between the two memory compartments. These include heterogeneity in function, anatomical location and phenotype, which probably relate to differential environmental cues during the early priming events as well as the later differentiation phases. Detailed definition of the molecular and cellular signals involved in the development of immunological memory, and the relative contributions of different memory subsets to protective immunity, remains an important goal.

Animals↗
PubMed2006

Why do B cells mutate their immunoglobulin receptors?

B cells have the unique ability to acquire large numbers of point mutations in the variable segment of rearranged immunoglobulin (Ig) genes during a germinal center reaction. It is broadly accepted that somatic hypermutation (SHM) and affinity maturation are required to generate memory B cells and to produce antibodies capable of accomplishing the host defense functions of the humoral component of the adaptive immune system. However, several studies illustrate that low-avidity interactions between antigen and the B-cell receptor can induce deletion, receptor editing and a T-dependent immune response, suggesting that the high-avidity binding of antigen is not essential. If enhanced antigen binding is not essential for immune responses, what is the purpose of SHM? An alternative benefit of SHM might be to enhance the ability of B cells to track antigens expressed by rapidly mutating microorganisms.

Antibodies↗
PubMed2005

Imiquimod: a potential weapon against Dupuytren contracture.

Dupuytren disease is a proliferative fibroplasia of the subcutaneous palmar tissue, occurring in the form of nodular and cords. Evidence is certainly accumulating for raised levels in Dupuytren's tissue of growth factors known to stimulate fibroblasts, Interleukin-1, basic fibroblast growth factor, transforming growth factor-beta, prostaglandin-F2, prostaglandin-E2, platelet derived growth factor and connective tissue growth factor have been suggested to have a role. Immune modification of profibrotic cytokines would provide a novel means to treat dupuytren contracture. Imiquimod cream 5% (Aldara) is an immune modifier, that downregulates transforming growth factor-beta and fibroblast growth factor-2 (the two most important cytokine in producing fibrosis). Based on previous mentioned evidence we suggest: imquimod as a potential drug for dupuytren contracture treatment.

Adjuvants, Immunologic↗
PubMed2006

Immunoglobulin is a highly diverse self-molecule that improves cellular diversity and function during immune reconstitution.

Paradoxically, human B cell immune deficiencies are associated with increased susceptibility to viral and fungi infections, which are T cell immunity related infections. Also, some viral infections occurring in immune depressed patients such as cytomegalovirus infections are recommended to be treated with intravenous immunoglobulin (IVIg) in combination with antiviral therapy. This fact has no clear biological explanation but it has been shown to be successful. Recently, B cells and immunoglobulin were identified as essential elements driving T cell receptor (TCR) diversity generation. Idiotype peptides of B cell immunoglobulin may be the driving force for the antigen presenting function of B cells and other antigen presenting cells to influence the T cell repertoire. This seems to be another relevance of Jerne's idiotypic network and another function of immunoglobulin. Since T cells function depends on the diversity of the TCR repertoire, means to increase the diversity of the T cell repertoire may improve T cell function in situations characterized by a contracted TCR repertoire, such as AIDS, primary immunodeficiency, cancer, autoimmunity and following chemotherapy and hematopoietic precursors transplantation. The clinical hypothesis here put forward is that B cells and/or immunoglobulin may be used therapeutically aiming to increase and potentially to restore T cell repertoire diversity improving T cell function in situations implicating a contracted T cell repertoire. The fact that immunoglobulin influence the composition of T cell repertoire by increasing its diversity allows a much wider application of this molecule in the clinical practice. Here is presented a novel reasoning for the use of IVIg in humans, which should be explored. All the situations where immune reconstitution occurs are potentially a target for this therapeutically mechanism, aiming to fast and improve the diversity of the reconstituted immune repertoires. This new role of Ig molecule, an old and widely therapeutically used molecule, may help to explain several effects that IVIg have in the T cell compartment, such as modulation of the activation and function of effectors T cells. The idea that immunoglobulin is essential in the generation and maintenance of a diverse compartment of T cells, affecting T cell function via that mechanism suggests a promising approach to medical conditions involving immune reconstitution. Furthermore, it represents a new paradigm of understanding the immune system as a complex, interdependent web of cells/cell products that inter-affect each other generation, function and survival.

Animals↗