George D. Snell

The influence of the gonads and adrenal glands on the immune response to skin grafts.

Summary The congenic strain pair C57BL/10Sn and BIO-129 (12M) differ from one another at the histocompatibility-12 (H-12) locus. Earlier work has shown that in this strain pair females reject allografts more consistently and more rapidly than males. This study is concerned with the effects of gonadectomy and adrenalectomy on the rejection by preimmunized B10-129(12M) mice of C57BL/10Sn skin allotransplants. Immunized unoperated or sham operated females showed, as expected, a higher per cent of rejections and a shorter rejection time than the comparable male group. Oonadectomy, adrenalectomy, and combined orchiectomy-adrenalectomy substantially increased the strength of rejection of males and, to a lesser extent, the strength of rejection of females. Adrenaleetomizcd and gonadectomized- adrenalectomized males and females showed essentially similar rejection patterns. Following gonadectomy alone, the per cent of rejections by females was higher than the corresponding male group, but the rejection rate was slower. Transplanting testes into oophorcctomized females had a greater effect than transplanting ovaries into orchiectomized males. Oophorectomized females with transplanted testes showed a significantly smaller rejection per cent than oophorectomized females without transplants. In contrast, orchiectomized males receiving transplanted ovaries showed a per cent of rejection not significantly different from orchiectomized males without transplants, although the rejection pattern of the rejecting portion was significantly slower than that of the male orehieetomy group

Histocompatibility genes of mice. VI. Allografts in mice congenic at various non-H-2 histocompatibility loci.

Using a panel of congenic resistant mice differng from C57BL/10ScSn at the H-1, H-3, H-4, H-7, H-8, H-9, H-10, H-11, H-12, and H-13 histocompatibility loci, the median survival times of skin allografts from and to C57BL/10ScSn were obtained. The following observations were made: 1. The strengths of the barriers imposed by the non-H-2 histocompatibility loci were quite variable, the median survival times for the various loci ranging from 15 to > 300 days. 2. The reciprocal graft rejections across non-H-2 burriers were often quite differet. BIOBY mice rejected C57BL/10ScSn skin with a median survival time of 15 days. C57BL/10ScSn mice rejected B10BY skin with a median survival time > 250 days. 3. The longer the median survival time, the greater was the range in survival times of individual grafts. 4. The rejection time of females of a given strain was frequently shorter than that of males. 5. Preimmunization with donor thymocytes increased survival of recipients of tumor allografts and, except in the case of the weakest histocompatibility differences, shortened the survival of skin allografts. 6. Injection at intervals of 1 week of 1, 2, and 4 X 105 thymocytes was less effective in protecting against a subsequent tumor allograft than 10 times these numbers of cells. However, an additional increase the cell dosage did not further increase the protection. 7. Skin grafted 7 days after immunization was rejected faster than skin grafted 14 days after immunization. Skin grafted after triple immunization was rejected faster than skin grafted after single immunization. 8. The strengths of rejection of skin and tumor across non-H-2 histocompatibility barriers paralleled one another.

Ly-6.2: A New Lymphocyte Specificity of Peripheral T-Cells

A new cell-membrane alloantigen determining locus, Ly-6, has recently been described, and the single specificity Ly-6.2 has been defined by the serum (BALB/c× A)F1 anti-CXBD. Using both fluorescence and cytotoxicity, we found this specificity predominantly on peripheral (extrathymic) T cells, as tissues react thus: thymus, 0–5 percent; spleen, 25 percent; lymph nodes, 69 percent; bone marrow, 15 percent. These reactions agree with the proportion of (Thy+, Ig−) cells present in these tissues. Cortisone-resistant thymus cells were positive. Absorption studies with thymus cells demonstrated the sparse or absent representation of Ly-6.2 on intrathymic T cells. Examination of spleen and lymph node cells from T cell-depleted C57BL/6 mice (after in vitro treatment with anti-Thy-1 serum or examination of tissues of C57BL/6-nu/nu mice) also showed a depletion of Ly-6.2+ cells. Conversely, removal of Ig+ B cells, which caused a relative increase in the number of T cells in the residual population, also increased the number of Ly-6.2+ cells. Additive effects of anti-Thy-1.2 and anti-Ly-6.2 could not be demonstrated, which suggests that the same population was Thy-1.2+, Ly-6.2+. However, additive effects could be shown with an anti-Ia serum and anti-Ly-6.2. The Ly-6.2 specificity is not found on red cells, liver, brain, or antibody-forming cells, but has been identified on a T-cell (but not B-cell) tumor and on kidney. Ly-6.2 can therefore be considered to be a marker for peripheral T cells, and it differs from the Thy-1 and the Ly-1,2,3, and 5 specificities in its relative absence from the thymus.

Genetic nomenclature for the H-2 complex of the mouse

The H-2 complex (system, Snell and Stimpfling 1966) represents a segment of chromosome 17 delimited by the H-2K and H-2D loci (Table 1). The complex is split by the Ss locus into two ends, the K end between H-2K and Ss, and the D end between Ss and H-2D. The term end can also be used to indicate the direction; thus the K end could mean the direction from the Ss locus toward the centromere, and the D end the direction from the Ss locus toward the telomere. The H-2 complex is composed of regions, subregions and loci. An H-2 region is a segment of the H-2 complex delimited by recombination and consisting of a marker gene and an undeterminate number of neighboring loci. The H-2 complex is to be divided into four regions, K, /, S and D, defined by marker genes H-2K, Ir-lA, Ss and H-2D, respectively. Subregions of a given region are segments identified by distinct but functionally related marker genes and separated from each other and the other regions by recombination. The I region is to be divided into two subregions, Ir-lA and Ir-lB, formerly termed Ir-1 and Ir-IgG, respectively. It is assumed that each region or subregion contains at least one locus,

The cumulative effect of histocompatibility antigens.

SUMMARYIn order to study the cumulative effect of mouse histocompatibility antigens, donor-host combinations were utilized which differed at 2, 3, 4, and multiple histocompatibility loci. Double difference pairs involving the Y-linked and one of several autosomal loci were produced by grafting from

Hemagglutination and cytotoxic studies of h-2. I. H-2.1 And related specificities in the ek crossover regions.

H-2 Specificities 23, 25, 11, 1, and 5, when arranged in this order, form an inclusion or subtype system, with 23 showing the narrowest distribution. Three of these specificities, 23, 25, and 11, are assigned to the K crossover region; the other two usually are assigned to the E region. Because of ambiguities in regard to 1 and 5, these specificities were selected for detailed study. Our panel of strains included two, PL/J and SM/J, with new alleles designated, respectively, H-2u and H-2v. Included also was strain B10. Y, previously typed as H-2q, but which now has an allele similar to or identical with H-2p. We provisionally call it pa. The panel did not include n in terms of which H-2.1 was originally defined. However, alleles p and n are similar, and our anti-p and anti-pa sera contained antibodies with reactions closely approximating those expected of an anti-1. Recipients for the production of antisera were selected to exclude as many antibodies as possible other than 1. Antisera were analyzed by direct hemagglutination and cytotoxicity against standard panels of cells. Many were also analyzed by in vivo hemagglutination absorption, and some, by quantitative in vitro cytotoxic absorption. Antisera made against alleles p, pa, s, v, and o were 1-like, in the range of their reactions, but showed individual differences. An antiserum made against allele q also contained a 1-like antibody, although it was complicated by the presence of anti-11. Antisera made with p as one parent of the recipient and with s as the donor (and also in the reverse combination) contained 1-like antibodies. We refer to these as blocked anti-1 sera. All unblocked anti-p or anti-pa sera reacted by hemagglutination with s, and one was fully absorbed by s. The individual differences in the reaction patterns of the antisera were largely confined to the 1-positive, 23-negative alleles. We refer to these as 1-intermediate alleles. Reactions with these alleles were often weak. With the 1-positive, 23-positive alleles (designated 1-complete alleles), except for some weak reactions by the blocked sera, the reactions were consistently strong. The differences in strength of reactivity between 1-intermediate and 1-complete alleles were particularly clear in the cytotoxic absorption tests. We suggest as a possible explanation a unidirectional cross reaction between 1 and 23. Crossover allele o received 1, but not 23, from 1-complete allele k; as would be predicted, it behaved like a 1-intermediate. We suggest that the variability of the reactions of the 1-intermediate alleles reflects mutational variation in their 1 sites, sufficient similarity remaining so that cross reactions occur, however. This hypothesis also explains the formation of 1-like antibodies in blocked combinations. The 1-complete alleles, because their EK regions trace through successive

Histocompatibility genes of mice. Vii. H-13, a new histocompatibility locus in the fifth linkage group.

A new histocompatibility locus, H-13, in linkage group V is described. The locus is identified by the congenic strain pair C57BL/10ScSn and B10.129(14M). It is moderately “strong” as compared with other non-H-2 loci. The order of the genes in linkage group V used in this study is a H-13 un we H-3. There is some evidence suggesting a possible third, rather weak histocompatibility locus between H-13 and H-3. There is also evidence suggesting interactions between the histocompatibility loci in this region. Whereas transplants from C57BL/10 to 14M (H-13a to H-13b in the presence of H-S‘) are strongly resisted, transplants from B10.LP-a to B10.LP (H-13a to H-13b in the presence of H-3b) are accepted with scarcely a trace of resistance. This has been demonstrated by both skin grafts and marrow transplants.

Histocompatibility genes of mice. V. Five new histocompatibility loci identified by congenic resistant lines on a C57BL/10 background.

A new group of congenic resistant (CR) lines of mice, differing one from another primarily by differences at single histocompatibility loci, has been produced by appropriate crosses. One parent in every case was strain C57BL/10 which provides the genetic background for the lines. For the other parent, with certain exceptions which do not concern us here, lines were selected which, like C57BL/10, have been typed as H-2b. The lines were inbred strain 129/Rr, and congenic strains C.B6, with H-2b on a BALB/c background, and D2.W, with H-2b on a DBA/2 background. Of the 20 CR lines produced from these crosses, seven are described for the first time in this paper. These serve to identify five new histocompatibility loci, herewith assigned the symbols H-7, H-8, H-9, H-10, and H-11. These lines vary substantially in the barrier which they oppose to C57BL/10 leukemic homografts, but except for line B10.C(47N) which differs from C57BL/10 at H-7, are all substantially “weaker” than lines characterized by the previously identified loci. They differ not only in “strength” of the allogeneic barrier, but also in the manifestation of this barrier in the two sexes. There are always more deaths from leukemic allografts in males than in females, but the difference is relatively slight in strain B10.129(9M), differing from C57BL/10 at H-10, and very marked in strain B10.C(45N), differing from C57BL/10 at H-9. A summary of the lines used in this study will be found in Table 7.

Histocompatibility genes of mice. XI. Evidence establishing a new histocompatibility locus, H-12, and new H-2 allele, H-2bc.

SUMMARY Strain B10.129(12M) is a congenic resistant strain differing from its partner strain, C57BL/10 or B10, by a rather weak histocompatibility locus. The locus is unusual in that the sex difference in the response to grafts is especially pronounced. Preimmunized females are strongly resistant to skin or tumor transplants; preimmunized males are not. Evidence presented herewith shows that B10.129(12M) identifies a new histocompatibility locus. This already has been provisionally designated H‐12; this usage is now confirmed. The allele of B10.129(12M) is assigned the symbol H‐12b. Congenic resistant strain B10. 129(6M) is also H‐12b but in addition carries a minor H‐2 difference from B10. Strain B10 is H‐2b; strain B10. 129(6M) has a new H‐2 allele, derived from the 129 parental strain, to which the symbol H‐2bc is assigned. Strain B10. 129(6M), unlike B10, also reacts with TL antisera. Presumably the Tla allele of 129, which determines the TL.2 antigen, was brought in with the H‐2 allele to which it is closely linked.

The distribution of thirteen H-2 alloantigenic specificities among the products of eighteen H-2 alleles.

SUMMARY Serological analyses have been carried out to define better the occurrence of certain known H-2 antigenic specificities among the products of the known H-2 alleles. A total of 57 additions or corrections to the chart of H-2 specificities has been made, involving H-2 specificities 5-9, 16, 17, and 27-31. One new specificity, H-2.18, which is confined to the H-2r type, has been defined. The serum serological variant type associated with each H-2 allele is also included in the H-2 chart