The immune response of allophenic mice to the synthetic polymer L-glutamic acid, L-lysine, L-phenylalanine. II. Lack of gene complementation in two nonresponder strains

The genetic control of the immune response of inbred strains of mice to certain antigens has been demonstrated to be governed by a set of Ir genes linked to the major histocompatibility complex (H-2) of mice (1,2). Until recently, the control was thought to be governed by single, dominant genes, located within the I region of the H-2 complex. Merryman et al. (3) originally demonstrated that the immune response to the synthetic terpolymer L-glutamic acid, L-lysine, L-phenylaline (GLφ) is under dominant, H-2-linked Ir gene control (4-7). This was shown both by crossing two nonresponder parental strains to produce responder offspring in the F(1) generation, and by the analysis of appropriate recombinant stains of mice. The two complementing genes have been mapped in the IA and IC regions of the H-2 complex, and have been termed β and α, respectively (5,6). Thus, any strain of mouse may contain neither, one, or both genes. Only mice containing both genes are capable of responding to GLφ. It has been shown using F(1) hybrid and recombinant strains of mice, that the α- and β-genes can complement each other in either the cis (on the same chromosome) or in the trans (on different chromosomes) position (8). In this paper we report the results of studies aimed at answering the question of whether or not the α- and β- genes can complement each other when they are present in different lymphoid cells. To this end we have constructed allophenic mice composed of two nonresponder strains (A and C57BL/6), which show gene complementation in the F(1) generation. Allophenic mice are chimeras containing two cell types coexisting in a normal environment. The mice were tested for the specific cellular composition of the two parental cell types and were found to possess a complete range in the relative proportion of the two cell types. This report demonstrates that regardless of the mixture of cell types present in the allophenic mice, none of them were responders to GLφ. Thus no complementation of the α- and β-genes is seen when the two genes are present in different cells.

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Murine Immune Responses to Liver-Stage Antigen 1 Protein FMP011, a Malaria Vaccine Candidate, Delivered with Adjuvant AS01B or AS02A

Infection and Immunity ◽

10.1128/iai.01075-06 ◽

2006 ◽

Vol 75 (2) ◽

pp. 838-845 ◽

Cited By ~ 15

Author(s):

Clara Brando ◽

Lisa A. Ware ◽

Helen Freyberger ◽

April Kathcart ◽

Arnoldo Barbosa ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Cell Types ◽

Inbred Strains ◽

Clinical Malaria ◽

Cell Stage ◽

Liver Stage ◽

Inbred Strains Of Mice ◽

Ifn Γ

ABSTRACT Liver-stage antigen 1 (LSA1) is expressed by Plasmodium falciparum only during the intrahepatic cell stage of the parasite's development. Immunoepidemiological studies in regions where malaria is endemic suggested an association between the level of LSA1-specific humoral and cell-mediated immune responses and susceptibility to clinical malaria. A recombinant LSA1 protein, FMP011, has been manufactured as a preerythrocytic vaccine to induce an immune response that would have the effect of controlling parasitemia and disease in humans. To evaluate the immunogenicity of FMP011, we analyzed the immune response of three inbred strains of mice to antigen immunization using two different adjuvant formulations, AS01B and AS02A. We report here the ability of BALB/c and A/J mice, but not C57BL/6J mice, to mount FMP011-specific humoral (antibody titer) and cellular (gamma interferon [IFN-γ] production) responses following immunization with FMP011 formulated in AS01B or AS02A. Immunization of BALB/c and A/J mice with FMP011/AS01B induced more antigen-specific IFN-γ-producing splenocytes than immunization with FMP011/AS02A. A slightly higher titer of antibody was induced using AS02A than AS01B in both strains. C57BL/6J mice did not respond with any detectable FMP011-specific IFN-γ splenocytes or antibody when immunized with FMP011 in AS01B or AS02A. Intracellular staining of cells isolated from FMP011/AS01B-immunized BALB/c mice indicated that CD4+ cells, but not CD8+ cells, were the main IFN-γ-producing splenocyte. However, inclusion of blocking anti-CD4+ antibody during the in vitro restimulation ELISpot analysis failed to completely abolish IFN-γ production, indicating that while CD4+ T cells were the major source of IFN-γ, other cell types also were involved.

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A new allele of the lpr locus, lprcg, that complements the gld gene in induction of lymphadenopathy in the mouse.

Journal of Experimental Medicine ◽

10.1084/jem.171.2.519 ◽

1990 ◽

Vol 171 (2) ◽

pp. 519-531 ◽

Cited By ~ 87

Author(s):

A Matsuzawa ◽

T Moriyama ◽

T Kaneko ◽

M Tanaka ◽

M Kimura ◽

...

Keyword(s):

Recessive Gene ◽

Mutant Gene ◽

Inbred Strains ◽

Lymphoid Hyperplasia ◽

Lymphoid Cells ◽

Autoantibody Production ◽

Genetic Studies ◽

Inbred Strains Of Mice ◽

Backcross Populations ◽

Generalized Lymphadenopathy

Several mice with generalized lymphadenopathy were found in the CBA/KlJms (CBA) colony maintained at our institute. A new mutant strain of mice that develop massive lymphoid hyperplasia at 100% incidence within 5 mo after birth was established by crossing these diseased mice. Genetic studies on lymphadenopathy were conducted in F1, F2, and backcross populations from crosses between mutant CBA (CBA-m) and various inbred strains of mice. The results supported the control of lymphadenopathy by a single autosomal recessive gene. Since C3H/He-gld/gld (C3H-gld), MRL/MpJ-lpr/lpr (MRL-lpr), and C3H/HeJ-lpr/lpr (C3H-lpr) mice develop the same type of lymphoid hyperplasia, allelism of the mutant gene with gld or lpr was tested by investigating lymphadenopathy in F1 and backcross populations from crosses between CBA-m and C3H-gld, MRL-lpr, or C3H-lpr mice. The gene was confirmed to be allelic with lpr but not with gld. Interestingly, however, the mutant gene interacted with gld to induce less severe lymphadenopathy. Thus, the mutant gene was named lprcg, an lpr gene complementing gld in induction of lymphoproliferation. The genetic conclusion was supported by the same profile of surface markers of lymphoid cells with gld/gld, lpr/lpr, lprcg/lprcg, lprcg/lpr, and +/gld +/lprcg genotypes, as well as by massive lymph node hyperplasia and high titers of autoantibodies in the first four genotypes, but slight hyperplasia and insignificant autoantibody production in the last. The discovery of lprcg provided strong genetic evidence for the parallels between anomalous phenotypes of gld and lpr, and CBA/KlJms-lprcg/lprcg mice will contribute to elucidation of the mechanism of induction of the same abnormal differentiation and functions of lymphocytes by gld and lpr.

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ALLOANTISERUM-INDUCED INHIBITION OF IMMUNE RESPONSE GENE PRODUCT FUNCTION

Journal of Experimental Medicine ◽

10.1084/jem.139.3.679 ◽

1974 ◽

Vol 139 (3) ◽

pp. 679-695 ◽

Cited By ~ 45

Author(s):

Ethan M. Shevach ◽

Ira Green ◽

William E. Paul

Keyword(s):

Immune Response ◽

T Cells ◽

T Lymphocytes ◽

Cell Surface ◽

Glutamic Acid ◽

Gene Product ◽

Lymphoid Cells ◽

Immune Response Gene ◽

Ga Response ◽

Ir Genes

It has been previously demonstrated that alloantisera can specifically block the activation of T lymphocytes by antigens, the response to which is linked to the presence of histocompatibility (H) types against which the alloantisera are directed. Thus, strain 13 anti-2 serum can inhibit the activation of (2 x 13)F1 T lymphocytes by a DNP derivative of a copolymer of L-glutamic acid and L-lysine (DNP-GL), an antigen the response to which is controlled by a 2-linked Ir gene. It was proposed that alloantisera can inhibit T-lymphocyte antigen recognition through interference with the activity of immune response (Ir) gene products. In order to further study whether the inhibitory antibodies within the alloantisera are directed against H antigens or against the products of the Ir genes, we have examined whether the anti-2 serum can inhibit the function of an Ir gene (the L-glutamic acid and L-alanine [GA] gene), which is normally linked to strain 2 H genes when this gene occurs in an outbred animal lacking strain 2 H genes. In the majority of cases, the anti-2 serum was capable of inhibiting the in vitro proliferative response to GA of T cells derived from animals that were GA+2+, but the serum had little if any effect on the GA response of T cells from GA+2- animals. Furthermore, an antiserum prepared in strain 13 animals against the lymphoid cells of a GA+2- outbred animal was devoid of inhibitory activity on the GA response of cells from a (2 x 13)F1, while an antiserum prepared in strain 13 animals against the lymphoid cells of a GA+2+ outbred animal was capable of specifically inhibiting the response to GA. It thus appears that the inhibition of the GA response by the anti-2 serum is primarily mediated via antibodies directed toward strain 2 H antigens rather than antibodies specific for the product of the GA Ir gene. The mechanism of alloantiserum induced suppression of Ir gene function would then be by steric interference with the Ir gene product on the cell surface, rather than by direct binding to it. This conclusion implies that the products of both the H genes and the Ir genes are physically related on the cell surface. The implications of such a relationship in terms of the fluid-mosaic model of the lymphocyte surface are discussed.

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Inheritance of sperm head abnormality types in mice – the role of the Y chromosome

Genetics Research ◽

10.1017/s0016672300016864 ◽

1976 ◽

Vol 28 (2) ◽

pp. 189-198 ◽

Cited By ~ 57

Author(s):

Halina Krzanowska

Keyword(s):

Relative Frequency ◽

Relative Proportion ◽

Inbred Strains ◽

Nuclear Material ◽

Sperm Head ◽

Total Percentage ◽

Inbred Strains Of Mice ◽

Reciprocal Differences ◽

Sperm Head Abnormality ◽

Seven Generations

SUMMARYFour inbred strains of mice were used, differing in the total percentages of spermatozoa with abnormal heads (KE, 22·1%; C57, 26·4%; KP, 7·7%; CBA, 5·5%) and in the frequency distribution of abnormality types, as divided into four arbitrary classes. The most variable class 2 (narrow heads with canals inside the nuclear material) accounted for 47% of all abnormalities in KE strain, was common in CBA (29%) and almost missing in KP and C57 strains. F1 hybrids from the diallel crosses of these strains exhibited highly significant heterosis effects and significant reciprocal differences in the total percentage of abnormalities. The relative frequency of class 2 ranked in F1 hybrids in a similar order as calculated from the mid-parental values. After seven generations of backcrosses performed to introduce the Y chromosome from CBA to the genetical background of the KE strain, the total percentage of abnormalities was significantly reduced, although the relative proportion of class 2 was similar to that in KE strain. Also the Y chromosome from C57 strain, introduced into the genetical background of KE strain, caused a significant reduction of total abnormalities, but again the relative frequency of class 2 was not affected. It is concluded that the Y chromosome plays an important role in determining the total percentage of sperm head abnormalities, but does not seem to be involved in influencing specific abnormality types.

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Genetic control of endotoxic responses in mice.

Journal of Experimental Medicine ◽

10.1084/jem.147.1.39 ◽

1978 ◽

Vol 147 (1) ◽

pp. 39-49 ◽

Cited By ~ 53

Author(s):

J Watson ◽

M Largen ◽

K P McAdam

Keyword(s):

Genetic Control ◽

Genetic Locus ◽

Serum Levels ◽

Cell Types ◽

Inbred Strains ◽

Amyloid Protein ◽

Chromosome 4 ◽

Inbred Strains Of Mice ◽

Different Cell Types ◽

Stimulating Factor

A number of altered immunologic responses to lipopolysaccharide (LPS) in C3H/HeJ mice result from the expression in B lymphocytes of a defective genetic locus, termed Lps. Lps has been mapped to chromosome 4 between two loci, Mup-1 and Ps. As it is difficult to type individual mice for LPS responsiveness in more than one type of assay, we have utilized Mup-1 as a genetic marker to correlate LPS responses in mice to the expression of the Lps locus. Three nonlymphoid responses to LPS have been examined in 12 recombinant inbred strains of mice and in a backcross linkage analysis, and are all regulated by the expression of the Lps locus. These responses are hypothermal changes in body temperature, and the elevation in serum levels of a colony stimulating factor and the precursor of the secondary amyloid protein AA. Therefore, the initiation of LPS responses in different cell types in mice involve the expression of a common locus. These linkage studies provide a means for analyzing the genetic control of many of the diverse reactions of the endotoxic response to LPS.

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