Increased growth of RSV-induced tumors in chickens partially tolerant to MHC alloantigens

Chickens with B2B2 MHC genotypes were made partically tolerant to B5 MHC cell-surface antigens and the fate of their Rous-sarcoma-virus (RSV)-induced tumors was determined. B2B2 chickens partially tolerant to viable or lysed white blood cells (WBC) or viable red blood cells (RBC) from B5B5 chickens had a significantly higher incidence of tumor progression than untreated, PBS-treated, or B2B2 chickens inoculated with WBC from other B2B2 chickens. The criteria for tolerance were absence of antibody titer to the cell type inoculated and acceptance of allografts from B5B5 donors by B2B2 chickens. Graft-vs-host reactions occurred only in B2B2 chickens inoculated with viable WBC from B5B5 chickens. It appears that B2B2 chickens partially tolerant to B5 antigens failed to mount a successful immune response to RSV-induced tumors partly because of a B5 MHC antigen(s) cross-reacted with a tumor associated antigen(s) thereby severely limiting B2B2 host recognition of the tumor as foreign. Since WBC and RBC cell-surface antigens appear to contribute similarly to the effect, the B-F- region of the MHC may be involved.     

Increased growth of RSV-induced tumors in chickens partially tolerant to MHC alloantigens

Chickens withB ² B ² MHC genotypes were made partially tolerant to B₅ MHC cell-surface antigens and the fate of their Rous-sarcoma-virus (RSV)-induced tumors was determined.B ² B ² chickens partially tolerant to viable or lysed white blood cells (WBC) or viable red blood cells (RBC) fromB ⁵ B ⁵ chickens had a significantly higher incidence of tumor progression than untreated, PBS-treated, orB ² B ² chickens inoculated with WBC from otherB ² B ² chickens. The criteria for tolerance were absence of antibody titer to the cell type inoculated and acceptance of allografts fromB ⁵ B ⁵ donors byB ² B ² chickens. Graft-vs-host reactions occurred only inB ² B ² chickens inoculated with viable WBC fromB ⁵ B ⁵ chickens. It appears thatB ² B ² chickens partially tolerant to B₅ antigens failed to mount a successful immune response to RSV-induced tumors partly because a B₅ MHC antigen(s) cross-reacted with a tumor associated antigen(s) thereby severely limitingB ² B ² host recognition of the tumor as foreign. Since WBC and RBC cell-surface antigens appear to contribute similarly to the effect, theB-F- region of the MHC may be involved.     

src-specific immunity in inbred chickens bearing v-src DNA- and RSV-induced tumors

Serological data identify a single major histocompatibility complex (MHC) class I locus in cattle. Molecular data, however, demonstrate the presence of at least two cattle MHC (BoLA) class I loci. To investigate the number of transcribed BoLA class I genes, we amplified cattle cDNA by using a single MHC class I-specific primer that hybridized to a conserved region of exon 4 and a non-specific 3 primer. Six BoLA class I cDNAs have been cloned and sequenced from a Bos taurus bull heterozygous for BoLA class I serological antigens, demonstrating the presence of a minimum of three loci. Sequence comparisons suggested that one of these cDNAs may be an unexpressed allele or the product of a nonclassical locus.The nucleotide sequence data reported in this paper have been submitted to the GenBank nucleotide sequence database and have been assigned the accession numbers U01186 and U01187.     

TheB locus (MHC) in the chicken: Association with the fate of RSV-induced tumors

The fate of tumors induced by Rous sarcoma virus (RSV) was determined in anF ₂ population segregating at three alloantigen loci. TheF ₁ resulted from crossing tumor-resistant RPRL line 6₁ (B ² B ² D ³ D ³ I ² I ²) with tumor-susceptible RPRL line 15₁ (B ⁵ B ⁵ D ⁴ D ⁴ I ⁸ I ⁸). Among theF ₂ segregantsB ² B ²,B ² B ⁵, andB ⁵ B ⁵, the percentage of chicks dying of terminal tumors (by 70 days post-inoculation) was 5, 26, and 93, respectively (P0.01). NeitherD orI genotypes nor sex significantly affected tumor growth. In chickens with terminal tumors, the incidence of metastatic lesions was also significantly associated withB genotypes. Thus, the MHC chromosomal region in the chicken appears to exert a crucial role in determining the outcome of RSV-induced tumors.     

Genetic control of the immune response in lines of chickens selected for graft-versus-host competences

The immune response of chickens to goat erythrocytes has been examined. The H line selected for high competence of graft-versus-host reaction (GVHR) showed higher immune responses than the L line selected for low GVHR competence. It appeared also that immune responses were controlled by the B blood group locus, which is the major histocompatibility locus in chickens. The relative immune responsiveness of B genotypes were B ¹¹/¹¹> B ⁹/ B ¹¹> B ⁹/B⁹.
Treatment of antiserum with 2-mercaptoethanol (2-ME) proved that the difference in immune responses between lines was due mainly to the 2-ME resistant antibody and that the difference between the B genotypes was due to the 2-ME sensitive antibody.     

Genetic control of immune responses in chickens

The immune response of inbred lines of chickens to the terpolymer poly(glu⁶⁰ala³⁰tyr¹⁰) and copolymer poly(glu⁶⁰ala⁴⁰) was determined. Of six lines immunized, one (line 7) contained birds that either did not respond or were low responders to two injections of 1 mg each of the polymers in Freund's complete adjuvant. As indicated by radioimmunoelectrophoresis, low responders produced a 7S response, although the switch from 17S (high molecular weight immunoglobulin) to 7S antibody production was slower than in high-responder lines. Analysis of the distribution of responders and nonresponders in F₂ generations produced byinter se mating of F₁ hybrids of line 7 with high-responder lines, showed that immune responses were clearly determined by certain alloalleles of theB blood group locus, the major histocompatibility system in the chicken.     

Genetic interaction between Non-MHC T- and B-cell alloantigens in response to rous sarcomas in chickens

Chickens of Regional Poultry Research Laboratory (RPRL) inbred line 6₃ regress sarcomas induced by Bryan high-titer Rous sarcoma virus to a greater extent than chickens of line RPRL 100, although these lines are identical for the major histocompatibility B complex. They differ, however, at three independent autosomal loci: Ly-4 and Th-1 determine the surface alloantigens of partly overlapping subsets of T lymphocytes, and Bu-1 determines a surface alloantigen of B lymphocytes. The association of genotypes at these loci with quantitative variation in their ability to regress Rous sarcomas was tested in segregating F₄ generation progeny derived from crosses of lines 100 and 6₃. The Ly-4 and Bu-1 genotypes showed association with Rous sarcoma regression, but the Th-1 genotype did not. Chickens of the Ly-4 ^a/Ly-4 ^a, Bu-1 ^b/Bu-1 ^b and Ly-4 ^b/Ly-4 ^b, Bu-1 ^a/Bu-1 ^a genotypes had a significantly higher regressor ability than the other two double homozygous genotypes. These results indicate that higher regression is associated with (1) interaction between the Ly-4 and Bu-1 loci, and (2) complementation between either the line 6 Ly-4 ^a allele and the line 100 Bu-1 ^b allele, or the line 100 Ly-4 ^b allele and the line 6 Bu-1 ^a allele.     

Genetic control of the immune response to staphylococcal nuclease

Summary Antibody responses of inbred strains of mice to staphylococcal nuclease were studied by isoelectric focusing in polyacrylamide gels followed by in situ labeling of focused antibodies with radioactive antigen. All A/J mice examined produced antinuclease antibodies of limited heterogeneity, and although there was individual variation in the focusing patterns observed, a characteristic spectrotype produced by all of the animals could be discerned. In order to determine the possible relationship between this characteristic spectrotype and the cross-reactive idiotypes of A/J antinuclease antibodies previously described (7), focused antibodies were also examined with a radioactively labeled pig anti-(A/J antinuclease) anti-idiotypic antibody preparation. Using this reagent, similar spectrotypes to those observed for antigen binding were seen in all of the individual A/J sera, suggesting that cross-reactive idiotype expression is a reflection of the characteristic spectrotypes observed. The same labeled anti-idiotypic reagent revealed characteristic but different spectrotypes when used to develop focused antinuclease antibodies from individual mice of other strains, suggesting that the use of similar variable region structures may be a common feature of the antinuclease response in mice of different allotypes. These studies thus provide a structural basis for the genetics of idiotype expression defined previously by serologic analysis.     

Genetic control of the immune response

The participation of cells from bone marrow and thymus in the antibody response to haptens was studied in two inbred strains of mice: poorly (CBA/J) and well (B10.LP) responding to immunization. The cell transfer experiments showed that the genetic regulation of the antihapten response under study, was bound directly to lymphatic cells of the immune system. For transfer of the good response it was essential that the thymus and bone marrow cell mixture contained bone marrow cells from well responding donors. Furthermore, the effect of endotoxin on antibody formation was studied in both well and poorly responding strains. It was found that endotoxin enhanced the antibody formation in both strains similarly so that the finεl differences between the levels of antibodies formed in both strains remained unchang d. Finally, it was demonstrated that endotoxin played the most important role in the primary stimulation, where the highest increase of the antibody response was obtained.     

Genetic control of the immune response

(I) The influence of the dose of antigen on the amount of antibodies produced was studied in two inbred strains of mice that were different with respect to the ability to produce antibodies top-aminobenzoic acid, i.e. well responding strain B10.LP and poorly responding CBA/J strain. Similar dependence between the dose of antigen and the antibody titre was demonstrated in both strains. (2) It was found that the type of reaction to the antigenic determinant (i.e. hapten) appeared to be a constant property of the inbred strain and that it did not change during the long period of the immunological maturity of the organism. (3) Antibodies of 19S type (2-mercaptoethanol sensitive) were formed in sera of both inbred strains, particularly in strain B10.LP, even after the third adjuvant immunization. Antibodies of 7S type appeared to be partially 2-mercaptoethanol sensitive, however, the major part was resistant to this agent. No 7S, 2-mercaptoethanol resistant antibodies were found in sera of the poorly responding strain CBA/J.     

Genetic control of the immune response

(1) Inbred strains of mice when immunized withp-aminobenzoic acid and sulphanilic acid bound by diazo-linkage to the same protein carrier molecule (bovine gamma globulin) differ in their ability to respond by antibody formation. The strains A and CBA/J form only low levels of antibodies to the haptens after immunization; in strains ScSN and B10.LP the same high titers of antibodies to both haptens were found under these conditions. The strain B10.D₂ forms antibodies well to sulphanilic acid, antip-aminobenzoic acid antibodies are formed only in very low quantity. (2) Individual mice of an inbred strain form a homogeneous population in respect of their capability or inability to form a particular antihapten antibody. The individual titers in a given inbred strain vary only slightly. On the contrary the noninbred strain H shows great variability both in quantity and quality of the immune response to the haptens. (3) The crossing of good and poor anti-hapten antibody producing strains shows in F₁; F₂ and B₁ generation, that the ability to produce antibodies againstp-aminobenzoic and sulphanilic acid depends on the genotype of a given individual. The ability to respond is transmitted to the offspring as a dominant trait. (4) There is no difference in the response to the haptens between males and females of the same strain. (5) The antibodies to the haptens in different strains of mice differ in the ratio of 2-mercaptoethanol sensitive and 2-mercaptoethanol resistant antibody. Dedicated to Academician Ivan Málek on the occasion of his 60th birthday     

Genetic control of the immune response to ferredoxin: linkage and mapping of T cell proliferation and antibody production genes to the MHC of mice

The genetics of the immune response in the mouse were studied by using the antigenically simple, stable, naturally occurring protein ferredoxin (Fd) from Clostridium pasteurianum. The immune status of mice primed and boosted with Fd was assessed by using two parameters of immunity: T cell proliferation and serum antibody production with the ELISA method. In both assay systems, the response has been shown to be H-2 linked: k, b, and s haplotypes respond to Fd, and H-2d mice are nonresponders. It is apparent that different immunoregulatory events modulate the response in the responder strains; these factors become evident in the recombinant analysis of the response and to date an immunoregulatory gene(s) has been mapped to at least the K/I-A subregions. F1 analysis demonstrated a gene dose-dependent response of the strains studied.     

Effect of spleen extracts on the immune response in chickens to Ancylostoma caninum larvae

Spleen extracts from WLH chickens nonsensitized and sensitized by repeated infections of Ancylostoma caninum larvae were injected separately into isologous recipients. Extracts from donors infected with repeated high dose (250 + 250 + 500) and low dose (125 + 125 + 250) of larvae induced a significant acquired protective immune response when compared to controls which received normal extracts. No significant difference was observed between the two experimental groups. The filariform Ancylostoma caninum larvae which can cause cutaneous larva migrans in man are found to be carried by a variety of paratenic hosts. Several studies from this lab have shown that the white leg horn (WLH) chicken successfully sustains and also responds immunologically to this parasite. The present authors have also shown that extracts of bursae of Fabricius and spleens of immunized chickens can induce immunity in syngeneic recipients. Here an attempt has been made to investigate whether repeatedly sensitized extracts of A. caninum infected chickens can cause expulsion of a challenge dose from the recipients.     

Genetic control of the murine immune response to cholera toxin

This study was undertaken to determine whether previously noted differences in the immune response of inbred strains of mice to cholera toxin (CT) might be under immune response gene control. A series of inbred, congenic, and intra-H-2I region recombinant mouse strains were tested for responsiveness to CT after i.p. immunization with 0.1 micrograms CT in alum. Samples of plasma were collected at intervals before and after priming and boosting. IgG and IgA anti-CT were measured by ELISA. In three different sets of congenic strains, the level of IgG anti-CT clearly depended on the H-2 haplotype of the strain rather than on any background or Igh genes. Strains with the H-2b and H-2q haplotypes were high responders, and strains with the H-2k, H-2s and H-2d haplotypes were low responders. Within the H-2 complex, the IgG anti-CT response was mapped to the I-A subregion with the use of congenic intra-H-2I region recombinant strains. In contrast to these results with IgG anti-CT, plasma IgA anti-CT levels were uniformly low and indeterminate. We conclude that the murine IgG anti-CT response is controlled by a locus within the I-A subregion of H-2--a remarkable finding, considering the known abilities of this toxin to bind to and to directly stimulate lymphocytes.