Analysis of Mechanisms of Maintenance of Neonatally Induced Tolerance to Foreign Alloantigens

Male-specific transplantation antigen (H-Y)-immune cytotoxic T cells of some individual CBA/H mice exhibit lytic activity on male and female allogeneic targets (e.g., H-2b). Neonatal tolerance to H-2b abrogates the ability of CBA mice to generate secondary H-Y-immune cytotoxic T cells, but such cell activity to third-party alloantigens and to Bebaru and influenza virus is not impaired. The results are discussed in relationship to dominant major histocompatibility complex-coded immune response gene effects on cytotoxic T-cell responses.

Section: Methodsmentioning

confidence: 99%

Neonatal tolerance to alloantigens alters major histocompatibility complex-restricted response patterns.

Müllbacher¹

1981

“…Originally, it seemed logical to ascribe tolerance to an elimination of potentially self-reactive lymphocyte clones through early contact with antigen, a view that has subsequently received substantial (2, 3) but not unchallenged (4,5) experimental support. Since the discovery of suppressor T lymphocytes (6), it has been amply documented that these play a role in several different models oftolerance involving MHC antigens (7)(8)(9)(10)(11)(12)(13). Given that a lymphocyte population containing suppressor T cells may effectively inhibit the activation of normal immunocompetent cells ("infectious tolerance"), it becomes a matter of some difficulty to determine the presence or absence of functional T lymphocytes within a population whose phenotype is suppressor.…”

mentioning

confidence: 99%

Functional clonal deletion in immunological tolerance to major histocompatibility complex antigens.

Nossal¹,

Pike²

1981

CBA (H-2k) mice were rendered tolerant to H-2d antigens by injection of (CBA X BALB/c)F1 spleen cells at birth. At intervals of 2 days to 12 weeks, the frequencies of anti-H-2d cytotoxic T lymphocyte precursor cells (CTL-P) in thymus and spleen were determined by using a limiting-dilution microculture assay system for CTL-P. This assay, utilizing irradiated H-2d stimulator cells and concanavalin A-induced spleen cell conditioned medium, was shown to be linear over the range 30 to 100,000 responder cells and uninfluenced by IJ-positive cells. A profound and long-lasting deficit in activatable CTL-P, first demonstrable by day 5 of life in the thymus and day 8-10 in the spleen, developed in mice rendered tolerant, reaching a greater than 95% reduction by 6 weeks. Functional clonal deletion thus seems to be at least as important in the tolerant state as suppressor T cells. Repeated in vivo administration of anti-IJk serum partially inhibited clonal deletion, suggesting either that suppressor T cells are actively involved in producing clonal deletion or that IJk-bearing cells in the donor inoculum or the host represent an important factor.

“…The means by which tolerance is assessed is also of importance. The Guttman et aL studies used direct in vivo assays of skin graft acceptance and tumor take (10); Gorzynski and Steele's work relied on a more indirect criterion, the ability to generate cytotoxic T lymphocytes against the putatively tolerated H-2 type in vitro (1,2), an assay which has been claimed to correlate with in vivo graft rejection (18). In the present study, we used in vivo assays similar to Guttman and coworkers' although more accurately quantifiable, which allow us to discriminate between first-set rejection and the ability to be primed for accelerated rejection of a second graft.…”

Section: Discussionmentioning

confidence: 99%

Is acquired immunological tolerance genetically transmissible?

Nisbet-Brown¹,

Wegmann²

1981

We have attempted to verify that acquired characteristics can be transmitted through the male germ line by using as a model system the vertical transmission of specific immunological tolerance to major histocompatibility antigens. Tolerant males were a tetraparental mouse and separated parabionts, in each case showing stable lymphoid chimerism. Tolerance in the progeny was assessed by two in vivo assays, rejection of cardiac allografts and clearance of "3'I-labeled tumor cells. We were unable to find evidence for heritability of the tolerant state in tetraparental or parabiont males, with either assay system.The recent work of Gorczynski and Steele (1, 2) has indicated that acquired tolerance to major histocompatibility antigens can be vertically transmitted through the male germ line for at least two generations, a finding which appears to violate Weisman's doctrine ofthe separation ofsoma from germ line. As a possible mechanism for this phenomenon, Gorczynski and Steele proposed a variant ofTemin's hypothesis (3, 4) concerning the possible role of type C RNA viruses in the transduction of genectic material.In view of the great importance of such a finding, if verified, we have attempted to reproduce this phenomenon with a somewhat different system. In our protocol, the tolerant male was a C3H/HeJ + BALB/cCr tetraparental mouse and was mated to normal C3H/HeJ females. The homozygous C3H/HeJ progeny were subsequently tested for tolerance of H-2d major histocompatibility antigens by their ability to reject BALB/cCr fetal heart grafts and by the kinetics of clearance of 131IdUrd-labeled L1210 leukemia cells (5).In this paper we report that the first-generation progeny were indistinguishable from normal age-matched homozygotes in their first-set rejection ofcardiac allografts and in their ability to be primed for immune clearance of tumor bearing the relevant antigen in vivo. Similar results were obtained in limited studies on heart graft rejection by the progeny derived from mating separated parabiont males with normal females. Thus, these results place strict limits on the general applicability of Gorczynski and Steele's theory. MATERIALS AND METHODSMice. C3H/HeJ, DBA/2J, and BALB/cCr mice were obtained from the Small Animal Breeding Program (The University of Alberta, Edmonton, Canada). Plugged female mice of strains C3H/HeJ and BALB/cCr and pseudopregnant females of strain ICR were obtained from the same source.Tetraparental Chimeras. Tetraparental mouse chimeras were made according to standard procedures (6). Briefly, eightcell-stage embryos of strains C3H/HeJ and BALB/cCr were obtained by flushing the oviducts and proximal uterine segments of female mice on the second day of pregnancy (day of plugging = day 0). The zonae pellucida of the recovered embryos were removed by brief exposure to acidic Tyrode's solution, pH 2.5, and pairs of embryos were aggregated in drops of Whitten's WK-14 medium under a layer of mineral oil. After in vitro culture for 24-36 hr, mosaic blastocysts were transferred surgic...