TheH-2 class II genes and the susceptibility to the development of pulmonary adenoma in mice

To determine the locus in theH-2 complex that affects susceptibility to the development of pulmonary adenomas in mice,H-2 congenic and recombinant strains of mice with A/Wy, BALB/c, C3H, and B10 backgrounds were subjected to treatment with urethane. The average number and the incidence of adenoma foci were recorded five months after the treatment. InH-2 congenic strains on the A/Wy background, the average number of adenoma foci per mouse was significantly higher in mice of the A/Wy, A/J, and A-Tla ^b (H-2 ^a ) strains than in A.BY (H-2 ^b ) mice. In BALB/c and C3H congenic strains, the strains carrying theH-2 ^k haplotype were more susceptible than those carrying theH-2 ^b haplotype. InH-2 congenic strains on the B 10 background, the average number and incidence of foci was also higher in haplotypesa, h2, k, andj than in haplotypesb, s, f, d, r, h4, i3, i5, and4. The average numbers of adenoma foci in (A/J × A.BY)F₁ (H-2 ^a /H-2 ^b ) and (B10 × B10.A)F₁ (H-2 ^b /H-2 ^a ) were intermediate between the numbers in the parental strains. In [B10.A (4R) × B10.A (3R)]F₁ (H-2 ^h4 /H-2 ⁱ³ ) and [B10.A (4R) × B10.A (5R)]F₁ (H-2 ^h4 /H-2 ⁱ⁵ ), the numbers of adenoma foci were higher than in resistant parental recombinants. These patterns of response to urethane matched the patterns of the immune response to lactate dehydrogenase-B (LDH-B) and immunoglobulin gamma 2a (IgG2a) proteins. These differences between mice in their susceptibility to the development of pulmonary adenomas is probably due to the polymorphism of the class II genes in theH-2 complex.     

Immunogenetic analysis ofH-2 mutations

Spleen cells carrying theH-2K ^b allele and sensitized against TNP-modified stimulator cells in vitro displayed a cytotoxic effect against TNP-modified target cells carrying a mutation in theH-2K ^b allele (haplotypesH-2 ^ba ,H-2 ^bd , andH-2 ^bf ). Similar crossreactivity in TNP-CML was observed in the reciprocal direction. Spleen cells carrying theH-2K ^k allele and sensitized against TNP-modified stimulators displayed a cytotoxic effect against TNP-modified target cells carrying a mutation in theH-2K ^k allele (haplotypeH-2 ^ka ) and vice versa. The effector cells in these assays were sensitive to anti-T cell serum in the presence of complement, and supernatants from immune cultures did not induce nonimmune cells to display a cytotoxic effect. Titration of effector cells from mutant and wild-type strains of theH-2 ^b haplotype indicated no detectable quantitative differences in their activities. These data demonstrate that crossreactivity in TNP-CML occurs in closely related allogeneic strains that have recently undergone mutation in theH-2 complex.     

Genetic control of acquired resistance to visceral Leishmaniasis in mice

A series ofH-2 and non-H-2 congenic resistant (CR) strains on a C57BL/10Sn background were infected with 10⁷ amastigotes ofLeishmania donovani. Non-H-2 congenic strains B10.LP-H-3 ^b and B10.CE(30NX) and (B10.LP-H-3 ^b × B10)F₁ hybrids showed a very rapid decrease in liver-parasite burdens beyond day 21. Parasite counts for these strains at day 35 were significantly lower than for all other strains tested. The rapid decrease in parasite numbers, massive lymphocellular infiltration into the liver and strong delayed hypersensitivity reactions to parasite antigens in strains congenic for a portion of chromosome 2 indicated that acquired immunity toL. donovani was controlled by a dominant gene at or near theIr-2 locus. In addition, B10.129(10M) mice, which differ from C57BL/10Sn at theH-11 locus, showed highly significant increases in parasite numbers at day 35. Other observations supporting the absence of acquired immunity in B10.129(10M) included negative delayed hypersensitivity tests to parasite antigens and the absence of lymphocellular infiltrate into the liver. Although the differences were not as pronounced,H-2 CR strains withH-2 ^b ,H-2 ^a , andH-2 ^k haplotypes also showed significantly greater decreases in parasite numbers by day 35 as compared to otherH-2 CR strains.     

Additional mapping of mouse chromosome 2 genes

The purpose of this work was to elucidate the genetic fine structure of the central portion of mouse chromosome (Chr) 2. Seven Chr 2 congenic mouse strains [B10.PA(L)-pa we un a ^t , B10.PA(L)-pa A ^w , B10.PA(L)-we un a ^t , B10.PA(J)-pa a, B10.FS-we A ^w , B10.C-we A ^w , and B10.YBR-a] were produced. Breeding studies were carried out using strains B10.PA(L)-pa we un a ^t and B10.LP-H-13 ^b to accurately determine the recombination frequencies between marker genes pa and we (1.9%±0.3), we and un (8.8%±0.5), and un and a ^t (4.5%±0.4) of strain B10.PA(L)-pa we un a ^t . These strains and other Chr 2 congenic strains were typed for immunologically defined loci using monoclonal antibody (mAb) C23 reactive with the gene product of B2m ^b T-lymphocyte clone C1 reactive with the gene product of H-3 ^a and H-3 ^c , and lymphocyte clone H1.8 reactive with the gene product of Hd-1 ^a . B2m and H-3 typing located a recombinational event separating [pa B2m H-3] from we (the order of bracketed genes is not known). Hd-1 typing indicated that Hd-1 maps distal to [H-42, H-44] and proximal to un. The gene order [pa, B2m, H-3], we, [H-42, H-45], Hd-1, un, H-13, a ^t , with H-44 mapping centromeric to Hd-1, is indicated by the data. Address correspondence and offprint requests to: R. J. Graff.     

The production,testing, and utility of double congenic mouse strains

Two new double congenic strains, B10-H-2 ^a H-7 ^b /Wts and B10-H-2 ^d H-7 ^b /Wts, were selected to differ from B10.A and B10.D2/o, respectively, at theH-7 locus. The survival time ofH-7-incompatible skin grafts is dependent upon theH-2 haplotype of recipient and donor.     

Study of H-2 mutations in mice. IV. A comparison of the mutants M505 and Hz1 by skin grafting and serological techniques

The line B6.M505 is congenic with C57BL/6JY and carries a mutant form of theH-2 ^b haplotype designatedH-2 ^bd . The mutant site 505 was located by the F₁ tests in theK end of theH-2 gene complex. The M505 mice are histoincompatible with the B6.C(Hz1) line (haplotypeH-2 ^ba ) carrying another mutation in theK end ofH-2 ^b . Inability of M505 to complement Hz1 in tests with B6 skin grafting is considered as an evidence that the same gene was altered by both mutations. The gained H antigens of two mutants can cross-react in vivo as revealed by accelerated rejection of Hz1 skin grafts by B6 recipients presensitized with M505 spleen cells. The lost antigenic determinants are not identical as shown by accelerated rejection of B6 skin grafts by Hz1 hosts preimmunized with M505 spleen cells. Absorptions of the antiserum ASY-015, (d×a) anti-i, anti-H-2.33 with M505 spleen cells did not clear forH-2 ⁱ ,H-2 ^b andH-2 ^ba , and absorptions with Hz1 did not clear forH-2 ⁱ ,H-2 ^b , andH-2 ^bd . These results show that changes of histocompatibility determinants may be accompanied by loss of some haptenic determinants in the Hz1 and M505 mutations.     

Thirteen new chromosome-7 congenic lines

Thirteen new congenic lines have been produced which have chromosome-7 segments introduced from different strains onto the C57BL/10Sn background. Sublines B10.P(61NX)C,D, and E received chromosome-7 segments from P/J, B10.CE(62NX) from CE/J, B10.SEC(64NX)A,C,E, and F from SEC/1Re, B10.SM(65NX) from SM/J, B10.WB(66NX) from WB/Re, B10.A(67NX) from A/SnGrf, B10.AKR(68NX) from AKR/SnGrf, and B10.K(69NX) from C3H.K. Isograft testing indicated that three sublines, B10.P(61NX)D, B10.CE(62NX)B, and B10.WB(66NX)B are histoisogenic, i.e., histocompatible within each line. With the exception of B10.A(67NX), B10.AK(68NX), and B10.K(69NX), which have not been isografted, the remaining sublines showed residual heterozygosity on isografting. The three histoisogenic lines have undergone F₁ testing and have been found to possess theH-4 ^a allele and new and distinct alleles at theH-1 locus. They have been designated B10.P(61NX)-H-4^a H-1 ^d , B10.WB(66NX)-H-4^a H-1 ^e , and B10.CE(62NX)-H-4^a H-1 ^f . Direct exchange of grafts has indicated the following genotypes: B10.A(67NX)-H-4^a H-1 ^b , B10.AK(68NX)-H-4^a H-1 ^b , and B10.K(69NX)-F-4^a H-1 ^b . The B10.SEC(64NX) and B10.SM(65NX) sublines have not been typed completely forH-4 andH-1. F ₁ testing or direct exchange of skin grafts indicated that B10.P(61NX)-H-4^a H-1 ^d , B10.WB(66NX)-H-4^a H-1 ^e , B10.A(67NX)-H-4^a H-1 ^b B10.AK(68NX)-H-4^a H-1 ^b and B10.K(69NX)-H-4^a H1 ^b possess nonon-H-1 histocompatibility differences from the G57BL/10 background.     

H-2 influences phenytoin binding and inhibition of prostaglandin synthesis

We have reported that susceptibility to glucocorticoid- and phenytoin-induced cleft palate and glucocorticoid receptor levels in mice are influenced by the H-2 histocompatibility complex on chromosome 17. Phenytoin competes with glucocorticoids for the glucocorticoid receptor and inhibits production of prostaglandins and thromboxanes. In this paper we have investigated whether, as in the case of glucocorticoids, phenytoin receptor levels and phenytoin-induced inhibition of prostaglandins are influenced by H-2 in a variety of mouse tissues. Using congenic strains varying only in the H-2 region, but otherwise having either the A/Wy(A) or B10(B) genetic background, we demonstrate here that phenytoin receptor content in the lung and liver is significantly higher in the strains with H-2 ^a (A/Wy and B 10.A) than in their corresponding H-2 ^b partners (A.BY and B 10). The H-2 complex also influences phenytoin-induced inhibition of the release of ³H-arachidonic acid and prostaglandin biosynthesis from thymocytes, prelabeled with ³H-arachidonic acid. Thus, these results suggest a similar genetic and biochemical pathway for the teratogenic action of both phenytoin and glucocorticoids.     

Experimental allergic encephalomyelitis in congenic strains of mice

Inbred mice and lines congenic to them for the major histocompatibility complex were similar in susceptibility to EAE except for moderate differences in two pairs. TheH-2 haplotypesq, s, andb occurred in inbred strains and in congenic lines of high, medium, or low susceptibility. It is concluded that the major histocompatibility complex does not control susceptibility to EAE in mice. Furthermore, the low susceptibility of DBA/1J mice was not enhanced by poly A-U.     

Complex genetic effect of B10.D2 (M504) (H-2dm1) mutation

Serological and capping experiments show that the strain B10.D2 (M504) carrying the mutant haplotypeH-2 ^dm1 has two molecules in the products of theD region: H-2D^dm1 and H-2L^dm1 which are detectable by anti-H-2.4 and by anti-H-2.28 sera, respectively. Both these molecules differ serologically from the H-2D^d and H-2L^d molecules of the original (nonmutant) strain B10.D2. A third molecule, different from H-2D and H-2L, was detected inH-2 ^d ,H-2 ^dm2 but not inH-2 ^dm1 products.     

An H-11-linked gene has a parallel effect on Leishmania major and L. donovani infections in mice

The courses of visceral infection following intravenous injection of Leishmania donovani amastigotes, or lesion growth following subcutaneous injection of L. major promastigotes, were examined in B10.129(IOM) (H-2 ^b, H-11 ^b) mice and compared with disease profiles observed in congenic C57BL/10ScSn(=B10) (H-2 ^b, H-11 ^a) and B10.D2/n (H-2 ^d, H-11 ^a) mice, and in BALB/mice. Possession of alternative alleles at H-11 and closely linked loci transformed the normal curing/healing phenotype of B 10 mice into a characteristically different noncuring/nonhealing phenotype affecting both visceral and subcutaneous infections in B10.129(10M) mice. In reciprocal radiation bone marrow chimeras made between the congenic B10 and B10.129(10M) strains, both cure and noncure phenotypes were transferable with the donor hematopoietic system. Although it was possible to demonstrate transfer of suppression with T-enriched spleen cells from day 61 L. donovani-infected B10.129(10M) donor mice into 550 rad syngeneic recipients, the pretreatment of mice with sublethal irradiation did not, as in the earlier studies of Scl-controlled L. major nonhealing or H-2-controlled L. donovani noncure phenotypes, have a clear or consistent prophylactic effect. Together with the progressive disease profile observed even for L. donovani at low parasite doses this suggests that, despite their ability to develop initial delayed-type hypersensitivity reactions to parasite antigen early in L. major infection, B10.129(10M) mice possess some inherent defect in ability to mount a cell-mediated response effective at the level of macrophage antileishmanial activity in vivo even when suppressor T cells are not generated. Further elucidation of this characteristically different noncuring/nonhealing phenotype may provide important insight into common events involved in the development of the cell-mediated immune response to both visceral and subcutaneous forms of leishmaniasis.     

H-2-associated differences in androgen-influenced organ weights of a and C57BL/10 mouse strains and their crosses

The influence ofH-2 haplotypes (in three-month-old males) on body weight, vesicular gland, testes, and thymus weight was investigated in A, B10, and B10.A strains and their respective F₁, F₂, and Bc progeny. The influence of theH-2 haplotypes was found to contribute to heterosis in the body weight.H-2 ^a/H-2 ^a males have a smaller vesicular gland and larger testes and thymus weight thanH-2 ^b/H-2 ^b males when groups with an identical or comparable genetic background are compared.H-2 heterozygous classes are closer to the parental strain with higher values for absolute organ weight; for relative organ weight, the heterozygous classes are intermediate or closer to the parental strain with lower values. This complex situation results from the simultaneous action ofH-2 haplotypes on both organ weight (Hom-1 effect) and body weight (heterosis), which probably operate through different mechanisms. Coat color genes were found to modify the penetrance ofH-2 influence on quantitative traits.     

Identification of a new CML target antigen controlled by a gene associated with theQa-2 locus

BALB/cBy anti-BALB/cJ spleen cells were tested in a secondary cellmediated lympholysis assay. The effector cells generated displayed a positive cytotoxic effect against Con A lymphoblasts from only those strains that were typed serologically as having theQa-2 ^a allele. Confirmation that the target antigen is controlled by a locus closely associated with or identical toQa-2 was obtained by the findings that target cells from B6.K2 (Qa-2 ^a,Qa-3 ^a) mice were lysed by the effector cells, while those from theQa-2, 3 congenic strain B6.K1 (Qa-2 ^b,Qa-3 ^b) were not. The fact that target cells from aQa-2-positive/Qa-3-negative strain (DBA/1,Qa-2 ^ai,Qa-3 ^b) were killed indicates that the target antigen is controlled, at least in part, by theQa-2 locus, not the Qa-3.There is no observedH-2 genetic restriction for this cytotoxic effect, since target cells which have theQa-2 ^a allele but differ from the stimulator cells at theH-2K, D, andI regions were lysed efficiently.     

Selective reversal of H-2 linked genetic unresponsiveness to lysozymes

Genes outside of the mouse major histocompatibility complex (H-2) were found to be capable of specifically reversing the previously described nonresponsiveness to hen egg-white lysozyme (HEL) owing to H-2 ^b immune response (Ir) genes. C3H.SW, BALB.B, and C57L, all of the H-2 ^b haplotype, showed responsiveness to HEL, but not to human lysozyme (H UL). Mapping of the reversing gene(s) was attempted by testing H-2 ^b recombinant inbred (RI) strains of mice carrying C3H, BALB, and C57L non-H-2 ^b genes. Analysis of the strain distribution pattern of responsiveness with both CXB and BXH RI strains was consistent with the location of the responsible site within the H-3 region on chromosome 2. The anti-HEL proliferative responsiveness in two H-3 congenic strains of mice, B10.C(28NX) ^SN and B10.C-H-3 ^{cH-3 a} , that have BALB/c genes within the H-3 region confirmed the mapping, as well as localized the reversing gene(s) near the Ir-2 gene. The data are discussed with regard to the site of expression of the reversing gene(s) and its mechanism of action.Abbreviations used in this paper MHC major histocompatibility complex - HEL hen egg-white lysozyme - Ir immune response gene - HUL human lysozyme - SDP strain distribution pattern - PFC plaque-forming cells; ₂ m, ₂-microglobulin - CFA complete Freund's adjuvant - PT-LN parathymic lymph nodes - RI recombinant inbred mice     

Hierarchy ofH-2 haplotypes governs inheritance of immune responsiveness to TNP-MSA

Production of indirect TNP-specific plaque-forming cells (PFC) in response to immunization with 2, 4, 6-trinitrophenyl (TNP) conjugated to autogenous mouse serum albumin (MSA) in complete Freund's adjuvant (CFA) is underH-2 control. On the C57BL/10 (B10) background,H-2 ^b andH-2 ^d strains of mice are high responders, whereasH-2 ^a ,H-2 ^k orH-2 ^y2 strains yield low levels of indirect TNP-specific PFC. An unusual pattern of inheritance has been revealed in B10 congenic mice: high responsiveness controlled byH-2 ^b is inherited recessively, while high responsiveness controlled byH-2 ^d is inherited dominantly. On the C3H and A strain backgrounds, high responsiveness controlled byH-2 ^b is partially recessive;H-2 ^b /H-2 ^a F₁ mice respond with 20%-40% of the high responderH-2 ^b response. Yet, high responsiveness controlled by theH-2 ^d haplotype remains dominant on the C3H background. A hierarchy of haplotypes in order of decreasing immune responsiveness to TNP-MSA is evident as follows:H-2 ^d >H-2 ^b >H-2 ^k ,H-2 ^a orH-2 ^y2 . The unusual patterns of inheritance in the TNP-MSA system reveal graded regulation of responsiveness attributable to bothH-2 and non-H-2 genes.     

H-2-linked genes determine the level of the primary in vitro anti-Mls response

The level of cell proliferation and interleukin-2 (IL-2) production observed in an anti-Mls mixed lymphocyte reaction between spleen cells from H-2 compatible, Mls incompatible mouse strains is determined by the H-2 haplotype of the mouse combination. Thus, while AKR (H-2 ^k) spleen cells stimulated strong M1s^a responses in H-2^k responder cells, AKR H-2b spleen cells stimulated no or negligible M1s^a responses in responder cells from H-2 ^bmouse strains. This effect was observed at the levels of IL-2 production and cell proliferation. The magnitude of the response observed using F₁ (H-2 ^k/H-2 ^b) responder cells was found to be a function of stimulator rather than responder cells. The poor stimulatory capacity of AKRH-2 ^bspleen cells was also shown not to be due to the loss of the stimulatory Mls ^aallele during the construction of the congenic strain from AKR and C57BL/6 parental strains. Using stimulator cells from a second series of congenic mice, we found H-2 ^b(strain DLLP) again to represent a poorly Mls^a stimulatory H-2 haplotype. In addition, H-2^q (DBA/1) cells displayed very poor Mls^a stimulatory potential while H-2^d (D1.C) cells were efficient Mls^a stimulators. Again the effect was shown to be at the level of the stimulator cells. In toto, our findings indicate that the H-2 ^kand H-2 ^dhaplotypes encode strong Mls^a stimulatory potential while the H-2 ^band H-2 ^qhaplotypes determine poor Mls^a stimulatory potential in primary in vitro responses, measured as cell proliferation and IL-2 production.Abbreviations used in this paper: CTL cytotoxic T lymphocyte - IL-1 interleukin-1 - IL-2 interleukin-2 - MLR mixed lymphocyte reaction - NMS normal mouse serum     

The Mouse H-2A Region Influences the Envelope Gene Structure of Tumor-Associated Murine Leukemia Viruses

C57BL/10 (B10) strains congenic at the mouse major histocompatibility locus (H-2) were injected with a modified ecotropic SL3-3 murine leukemia virus (MuLV) to determine the effect of the H-2 genes on the envelope gene structure of recombinant MuLVs. All tested strains rapidly developed T-cell lymphomas, and recombinant proviruses were detected in the tumor DNAs by Southern blot. The B10.D2 (H-2^d), B10.Br (H-2^k), B10.Q (H-2^q), and B10.RIII (H-2^r) strains exhibited a TI phenotype in which almost all tumors contained type I recombinants. These recombinants characteristically acquire envelope gene sequences from the endogenous polytropic viruses but retain the 5′ p15E (TM) gene sequences from the ecotropic virus. The parental B10 (H-2^b) strain, however, had a novel phenotype that was designated NS for nonselective. Only 30% of the B10 tumors had detectable type I recombinants, whereas a proportion of the others appeared to contain type II recombinants that lacked the type I-specific ecotropic p15E gene sequences. Studies of other B10 congenic strains with hybrid H-2 loci and selected F₁ animals revealed that the NS phenotype was regulated by a dominant gene(s) that mapped to the A region of H-2^b. These results demonstrate that a host gene within the major histocompatibility complex can influence the genetic evolution of pathogenic retroviruses in vivo.     

Specificity of cell-mediated transplantation reactions in rats detected by the macrophage adherence inhibition test

The macrophage adherence inhibition (MAI) test, previously described as a correlative to specific cellular immunity, has been used to study the specificity of primary cell reactions after allografting in rats. The adherence of sensitized peritoneal cells (PCs) from AVN rats (major histocompatibility haplotypeH-1 ^a ) bearing Lewis skin grafts (H-1 ^l ) was inhibited specifically by antigens from the graft donor and by those of the allogeneic strains BN (H-1 ⁿ ), BD V (H-1 ^d ), and DA (H-1 ^a ). Antigens of strain AVN, congenic strain Lewis. 1A (H-1 ^a ), and xenoantigens did not inhibit adherence. In general, positive reactions occurred during interaction of the sensitized PC with antigenic material sharing some components of theH-1 system with the graft donor. On the other hand, no crossreactions between individual rat strains were found when cytotoxic antibodies were tested after skin allografting. The negative MAI test in PC from AVN rats sensitized with skin allografts from the Lewis strain done with Lewis. 1A (H-1 ^a ) antigenic material, and the positive MAI test with antigenic material of the DA (H-1 ^a ) strain point to the possible existence of serologically undefined transplantation antigens participating in the cell-mediated reactions.     

MHC recognition by clones of Mls specific T-lymphocytes

To test whether M1s determinants, like other non-MHC or nominal antigens, are recognized by T-cells in association with H-2 determinants, the in vitro proliferative responses of T-cell lines and clones were studied. Lines and clones were prepared by soft agar cloning (B10.BR x BALB/c)F₁ (H-2^k/H-2^d, M1s^b/M1s^b) T-cells responding in a primary MLR to AKD2F1 (H-2^k/H-2^d, M1s^a/M1s^a) stimulator cells. All the T-cell clones obtained could respond equally well in a proliferative assay to the Mls^a determinant in association with the H-2 haplotype of either parent, i. e., DBA/2 (H-2^d, M1s^a), and AKR (H-2^k, M1s^a) both stimulated equally well. When the T-cell lines and clones were screened against stimulators from recombinant inbred (RI) strains, it became apparent that strains exhibiting the H-2^b, M1s^a genotype stimulated poorly or not at all. This shows that the T-cell response to M1s^a involves MHC recognition, and raises the possibility that the response to M1s^a can involve recognition of H-2 specificities shared between the H-2 ^k and H-2 ^d haplotypes.Abbreviations used in this paper MHC major histocompatibility complex - MLC mixed lymphocyte culture - IL-2 interleukin 2 - Con A concanavalin A - RI recombinant inbred Howard Hughes Medical Institute     

The role ofH-2 regions in overcoming tissue incompatibility

Neonatal transplantation tolerance to the products of theH-2 ^b complex was induced in B10.A (H-2 ^a ) mice. On the basis of the survival of skin allografts it was found that antigens determined by theD region of theH-2 ^b complex (of the B10.A(2R) strain) were most easily overcome and that tolerance to the products of theD end of theH-2 complex (of the B10.A(4R) strain) was also easy to induce. The antigens produced by theK end ofH-2 (of the B10.A(5R) and B10.A(3R) strains) represented a stronger incompatibility barrier and a difference in the entireH-2 ^b complex caused strongest resistance to tolerance induction. When tolerance to the products of the entireH-2 ^b complex was induced in newborn B10.A mice, and the neonatally treated animals were grafted simultaneously with five different grafts, those disparate at theK end ofH-2 and in the entireH-2 region were rejected in some animals, while the grafts disparate at theD end of H-2 remained intact in the same mice. No dependence on theI-J subregion was observed in this system. Furthermore, tolerance was more easily inducible in male than in female B10.A mice.