Judith Bard

HEMATOPOIETIC RECONSTITUTION IN A PATIENT WITH FANCONI'S ANEMIA BY MEANS OF UMBILICAL-CORD BLOOD FROM AN HLA-IDENTICAL SIBLING

THE clinical manifestations of Fanconis anemia, an autosomal recessive disorder, include progressive pancytopenia, a predisposition to neoplasia, and nonhematopoietic developmental anomalies.1 2 3...

Preweaning experience in the control of mating preferences by genes in the major histocompatibility complex of the mouse

The major histocompatibility complex (MHC) of genes of the mouse influences mate choice. Typically, inbred males prefer to mate with females that differ from themselves at this gene complex. Previous studies documenting differences between mating preferences of inbred and F2-generation males, as well as a possible effect of ambient mouse odors on preference, indirectly implicate rearing history as an influence in the determination of mating preference according to MHC types. To test directly the role of rearing history, entire litters were fostered onto parents of the same or different MHC types. Fostering of males onto parents of different MHC types reversed the natural preference; under these conditions, matings with females of the same MHC type as the fostered male were more frequent. Thus, male mating bias appears to be acquired during early development through exposure to parental MHC-controlled signals. Preliminary studies of mating biases in fostered females demonstrated a mating bias that was unaffected by fostering experiences. These studies indicate that the same set of genes involved in regulation of immune function also determines, in part, mate choice. A male bias in favor of females whose MHC types differ from the males parental MHC types could serve to promote heterozygosity at the MHC.

The scent of age.

In many species, older males are often preferred mates because they carry ‘good’ genes that account for their viability. How females discern a males age is a matter of question. However, for animals that rely heavily on chemical communication there is some indication that an animals age can be determined by its scent. To investigate whether there are changes in body odours with age, and if so their composition, mice were trained in a Y–maze to discriminate urine odours of donor mice of different ages: Adult (3–10 months old) and Aged (more than 17 months old). Trained mice could discriminate between these two age groups by odour alone. To determine the chemical basis for these discriminations, studies were performed using gas chromatography and mass spectrometry. These analyses demonstrated differences in the ratio of urinary volatiles with age. The most prominent differences involved significantly greater amounts of 2–phenylacetamide and significantly lower amounts of methylbutyric acids in Aged animals relative to Adult animals. Fractionating and manipulating the levels of these compounds in the urine demonstrated that the mice can distinguish age based on variation in amounts of these specific compounds in the combined urine.

Fetal H-2 odortypes are evident in the urine of pregnant female mice

The major histocompatibility complex (MHC) imparts to each mouse an individual urinary odor, called “odortype”, which reflects its MHC genotype. Perception of odortypes affects mate selection and embryonic implantation. Recent findings that odortypes tre expressed as early as one day of age suggested that they might already be expressed in utero. We now report that at 9–12 days of gestation, odortypes specified by paternal (non-maternal) MHC haplotypes become apparent in maternal urine. Thus, odortypes are expressed in utero, can be sensed even before birth, and may serve in familial identification and communication.

Effect of B2m gene disruption on MHC-determined odortypes.

Abstract Major histocompatibility complex (MHC) genes confer individual olfactory identity that can be detected with exquisite accuracy by mice. The fact that MHC genes themselves generate the characteristic odortype, rather than dedicated odor-determining genes, was supported in studies of point mutations in H2K and HLA transgenic mice, which evinced distinct odor profiles in olfactory assays. In this article we provide further evidence for a central role of MHC genes themselves in odortype specification by demonstrating that mice that are unable to express their genomic class I MHC genes because they lack β2-microglobulin are distinguishable by scent from otherwise identical mice which possess an intact B2m gene. This odortype disparity appears at 9–12 days of gestational age, the period in which the MHC is first detectable in fetal cells of normal mice.

A distinctive change in odortype determined by H-2D/L mutation.

Genetic polymorphism in the H-2:Qa:Tla major histocompatibility complex (MHC) region of chromosome 17 of the mouse is associated with constitutive variation of odortypes, defined as genetically determined body odors. The class I H-2K (K) gene is known to be implicated in odortype determination since mice can discriminate the odor of a K b gene mutant strain, C57BL/6-H-2 bml (bml), from that of the nonmutant C57BL/6 (B6) inbred strain (Yamazaki et al. 1983, 1986). Mice also discriminate odors of other B6 K b mutants (bm5, bm7, and bm8) from odors of nonmutant B6 mice (Yamazaki et al. 1990a,b). Since mutants may initiate rediversification of the K b gene, they offer a model system for studying the evolution of class I MHC diversity (Geliebter et al. 1986). The diversity of K alleles in natural populations suggests that mutants and recombinants are commonly preserved. A factor favoring propagation of a new mutation would be the provision of mutant carriers with a distinctive odortype that affects reproduction. Consistent with this hypothesis are data indicating that MHC congenic males generally prefer to mate with congenic MHC dissimilar females rather than with syngeneic MHC-identical females (reviewed by Boyse et al. 1991). Since such a mating bias, were it to occur in wild populations, should promote MHC diversity, the generality of mutation-induced odortype specificity warrants further investigation. For this reason we turned to other class I genes and studied the ability of mice to distinguish the odortype of BIO.D2-H-2 am1 (dml) mutant mice from that of B10.D2 (H-2d), the strain in which the H-2 ~ml class I mutant arose (Egorov 1967). This mutation has been mapped to the H-2D/L region and is unique among known H-2 mutations in that two class I transplantation antigens, D d and L a, are affected (McKenzie et al. 1977; Ivanyi and Demant 1978). H-2 am1 has been sequenced and shown to

Chemosensory Identity and the Y Chromosome

Genes in the extended major histocompatibility complex (MHC) of the mouse (H-2∶ Qa∶T1a) impart to each mouse an odor that reflects its genetic constitution at this region of chromosome 17. Sensory recognition of these differential odors influences reproductive behavior and evokes neuroendocrine responses critical to the maintenance of pregnancy. To determine whether other parts of the mouse genome contribute to individual odor, and so may similarly exert a selective force on loci other than the MHC, mice differing genetically only in their X and/or Y chromosomes were tested for individuality of scent in the Y-maze system previously employed to investigate MHC-related scent distinctions. It was found that the X and Y chromosomes each confer individuality of scent related to genotype, but differences at the H-2 locus are considerably more salient. Never-theless, chemosensory cues controlled by differences on the Y chromosome could play a role in individual recognition, mate selection, aggressive interactions, and perhaps other aspects of mouse chemosensory behavior.

MHC Control of Odortypes in the Mouse

Odortypes, defined as genetically-determined body odors that enable individuals of a species to distinguish one another by odor, are specified in part by polymorphic genes of the Major Histocompatibility Complex or MHC. The participation of the MHC in individual odor constitution may shed light on evolutionary and developmental functions of the MHC (Beauchamp et al., 1986; Boyse et al., 1987, 1991; Yamazaki et al., 1991). These functions have long been suspected to account for many non-immunological correlates of MHC polymorphism which have no obvious connection with the precisely defined immunological functions of the MHC (review in Boyse et al., 1983), but which may signify more rudimentary functions that preceded the specific adaptive immunity which is fully manifested only in vertebrates.

Analysis of the hairless mouse as a model for the effects of aging on the immune system

Studies into the effects of aging on the immune system are hampered by the lack of a suitable animal model that is readily available and cost efficient. The mutant mouse, hairless (hr/hr genotype), has been shown to undergo an accelerated thymic involution with accompanying immunodeficiency. Thus, this strain of mouse has been proposed as a model for studying the interactions of aging and immune function. We have investigated the effects of homozygous hr gene expression over time on the immune function of these mice. It was observed that homozygous hr gene expression had minimal effects on peripheral lymphocyte subset compositions but did appear to result in changes in thymic differentiation. Further, hr/hr mice displayed decreased proliferative responses to IL2 and mitogen stimulation, although cytotoxic responses (both NK and T cell mediated) appeared normal. These defects appear to be attributable to T helper cell dysfunction. Each of the changes found in hr/hr mice were distinct from those seen with age-matched control mice. Thus, the hr/hr inbred strain of mouse does not appear to be a suitable model for use in analyzing the effects of aging on the immune system.

Determination of Distinction Odortypes by Mutation of Class I and Class II MHC Genes

Genetic polymorphism in the H-2:Qa:Tla region of chromosome 17 is associated with constitutive variation of bodily odor phenotypes which permit individual olfactory recognition among mice (Boyse et al.1987). We previously found that differences in the MHC genes affect the mating choices of mice (Yamazaki et al. 1976, 1978, 1988; Andrews and Boyse, 1978; Yamaguchi et al., 1978), and that mice can be trained to distinguish arms of a Y-maze scented by odors from mice differing only in this genetic region (Yamazaki et al.,1979, 1982; Yamaguchi et al.,1981). We also showed a raised incidence of blockage of pregnancy or pseudopregnancy in mated females exposed to the scent of alien males whose MHC type differs from that of the mate (Yamazaki et al., 1983). As no known gene complex exhibits such vast diversity as the MHC, its potential as a major source for genetically based signals of individual identity is great.