摘要:

The establishment of a functional immune system with diverse antigen receptors is dependent on the V(D)J recombination activating gene products Rag-1 and Rag-2. These two proteins constitute the key lymphoid components required for the activation of antigen receptor rearrangement. Both Rag-1 and Rag-2 are required for the catalysis of the initial stages of V(D)J recombination. Thus, functional disruption of either the Rag-1 or Rag-2 genes by homologous recombination, leads to immunodeficiency due to lymphoid arrest at a stage prior to the recombination of the antigen receptor loci. In Rag-deficient mice, both B- and T-cell differentiation is eliminated due to the absence of antigen receptors. Lymphoid development can be restored by the introduction of rearranged antigen receptor transgenes that give rise to monoclonal populations of fully mature B- or T-cells. The absence of the major conventional populations of B- and T-cells from the Rag-deficient mice provided an excellent background for studying the molecular and cellular mechanisms of lymphoid differentiation. The Rag-deficient background has been used as a system for: the functional analysis of Rag-1 and Rag-2; studying the developmental functions of antigen receptors and other molecules of the immune system; the molecular analysis of the early stages of the B- and T-cell lineages; the co-development of lymphocytes with stroma cells; the identification of minor subpopulations of the developing immune system; the involvement of lymphoid populations in the onset of pathogenesis. In addition, the development of the“blastocyst complementation assay”methodology, based on the phenotype of the Rag−/−mice, allowed the functional analysis of numerous lymphoid specific components.

ISSN:0883-0185    

DOI:10.3109/08830189609061752

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

Since the discovery of SCID mice in 1983, numerous studies utilizing these mice were carried out. These investigations can be classified into two major groups. First, the analysis of the immune defect has revealed defective V(D)J recombination and defective DNA double-strand break repair, and has lead to the identification of the candidate gene for SCID mice. Second, the use of SCID mice to explore ways to introduce a murine or xenogeneic immune system into SCID mice by taking advantage of the immune deficiency of the mice has provided an animal model to examine thein vivofunction of transferred human or murine immune cells. In this review, we summarize the recent advances made in these two areas of SCID mouse research.

ISSN:0883-0185    

DOI:10.3109/08830189609061753

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

The T cell antigen receptor (TCR) transduces signals that mediate different responses depending on the stage of development of the T cell and the nature of the ligand it engages. The presence of multiple signal transducing subunits (CD3-γ-δ,-εandζchain) suggests the potential to control these responses by altering the subunit composition of the TCR.ζchain represents an especially important signalling molecule as it contains multiple signalling motifs within its cytoplasmic tail. The generation and analysis ofζdeficient (ζ−/−) andζ-transgenic mice has provided insight into the role ofζas well as the CD3 subunits in TCR surface expression, T cell activation and thymocyte development. Herein, we discuss the results from such experiments which suggest distinct roles forζchain and the CD3 components at different stages of T cell development.

ISSN:0883-0185    

DOI:10.3109/08830189609061754

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

Tdt deficient mice show lack of N region in V(D)J junctions of immunoglobulin and T cell receptor genes and revealed that“immature recombinase”in fetal stage would boil down to no more than a lack of Tdt. Although particular junctions which are thought to be created by homology-mediated joining are frequently observed, one fourth of junctions lacked even one bp of overlap, indicating the existence of a V(D)J joining pathway that is homology independent. Lymphocyte repertoire which express VH81X gene without N region is negatively selected, which shows that the repertoire of Tdt deficient mice is not a truly fetal repertoire. Positive selection of thymocytes is more efficient in Tdt deficient mice. Furthermore Tdt−/−mice produce significant amounts of anti-dsDNA antibodies as Tdt+/+mice, indicating that increased diversity of the third complementarity-determining region (CDR3) by Tdt is not essential for the expansion of precursor B cells programmed to produce anti-DNA antibodies.

ISSN:0883-0185    

DOI:10.3109/08830189609061755

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

B cell deficient animals obtained by various strategies of gene targeting were used to study the B cell development and examine the role of different immune compartments in the immune response to microbes.Study ofμMT, JHD,AST and JHT models of B cell deficiency, was essential in order to understand the role of pre-B cell receptor in B cell development, allelic exclusion and variable gene rearrangement regulation.In the immune response to influenza virus, a protective role of T cells in a total absence of B cell compartment, was revealed by studying the JHD -/- model. Further, it was established that a T cell compartment is sufficient to mediate the recovery from influenza infection.Examination of immune response inμMT and JHD models of definitive B cell deficiency to various blood stage Plasmodia species, showed that whereas B cells are not required for recovery from infection withP. chabaudi adami, P. vinckei petteriandP. chabaudi chabaudi(CB), B cell compartment is important in the later stages of infection withP. chabaudi chabaudi(AS). Studies carried out inμMT model suggested a possible role for Tγδsubpopulation in the immune response to blood stage malaria parasite.B cell deficiency models are valuable for understanding the normal and pathological immune response. Studies carried out inμMT model indicated that T cell responses are not significantly affected in the absence of B cells. These data can neither rule out a role for B cells in T cell priming, nor in triggering an effective T cell help for humoral response. Study of double homozygous mice deficient for B cells and FAS or IL-2 gene, pinpointed the role of B cells in pathogenesis of lupus-like nephritis and vasculitis from lpr mouse and in hemolytic anemia from IL-2 -/- mouse model, respectively.

ISSN:0883-0185    

DOI:10.3109/08830189609061756

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

ISSN:0883-0185    

DOI:10.3109/08830189609061757

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

Analysis of the B cell repertoire is complicated by the huge diversity inherent in the germ line determined combinatory. Making use of knockout technology, K-deficient mice have been obtained. They constitute a shrewd model to follow the expression of an Ig minilocus, such as theλone, in the normal condition compared with classical transgenic models. Indeed, in contrast to wild type mice, in which only 5% ofλB cells are produced, these mutant mice exclusively produceλpositive B cells. Although, theλlocus is well characterized and has a relatively simple organization, the mechanistic and selective pressures that govern its utilization are still poorly understood. The analysis of theλB cell repertoire in K-deficient mice, should therefore bring more conclusive informations. Here we present theλsubtype distribution in the various cellular compartments of the K-deficient mice, and discuss the rules that can be responsible for this distribution. Our recent data indicate that theλsubtype proportions in the bone marrow and the spleen result, for the major part, from mechanistic processes (i.e., recombinase accessibility, production of V-J functional joint and H/L pairings) while theλproportions found in the peritoneal cavity ensue from selective processes. Finally, the capacity to respond to various antigens is discussed from such a generatedλB cell repertoire.

ISSN:0883-0185    

DOI:10.3109/08830189609061758

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

Immunoglobulin Fc receptor (FcR)γsubunit is a component of low affinity receptor for IgG, FCγRIII, as well as high affinity receptor for IgE, FcεRI. This subunit is required for efficient surface expression of these FcRs on various cells in immune system. The FcRγ-deficient mice, generated by gene targeting in embryonic stem cells, exhibit multiple defects in FcR-mediated effector cell responses, including absence of phagocytic activity against opsonized red blood cells by activated macrophages, loss of antibody-dependent cell-mediated cytotoxicity manifested by IL-2-induced splenic NK cells, and unresponsiveness of mast cells to crosslinking of IgE on these cells. These results demonstrate an indispensable role of FcRγfor functional expression of FcRs, and clearly indicate the importance of FCγRIII as well as FcεRI for these effector functions. Since FcRγ-deficient mice is unable to mount the type II and type III hypersensitivity reactions, it is suggested that FcRs play pivotal roles in initiating these reaction cascades. The mutant mice should prove to be useful in evaluating FcRs in various humoral and cellular immune responses, and in developing new strategies for treatment of immunodeficiency as well as autoimmune disorders.

ISSN:0883-0185    

DOI:10.3109/08830189609061759

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor