Transfer of Acquired Tolerance to Skin Homografts in Mice.

Martínez, Carlos A.; Smith, Julius; Aust, J. Bradley; Mariani, T; Good, Robert A.

doi:10.3181/00379727-98-24134

Cited by 10 publications

(3 citation statements)

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“…If the state of unresponsiveness once induced by a single threshold dose of the antigen given during a critical phase of early postnatal life was found to be permanent and independent of further antigenic challenge, such evidence might be interpreted as indicating that a permanent adaptive change had occurred during the neonatal period prior to development of the capacity to recognize the proteins as foreign (or "non-self"), and that the change had been passed on to the progeny of the cells originally making the adaptation. Such a mechanism, proposed by Burner and Fenner (36), finds apparent support in the experiments showing induction of prolonged tolerance to homografted tissue by a single injection of viable reticuloendothelial cells at birth (11,(37)(38)(39)(40) and in experiments demonstrating tolerance of tumors induced by neonatal implantation (41,42). However, the data presented in this paper seem clearly to indicate that unresponsiveness to defined protein antigens, at least, is finite, and related in duration to the amount of the antigen provided at birth.…”

Section: Discussionmentioning

confidence: 82%

Immunological unresponsiveness in rabbits produced by neonatal injection of defined antigens

Smith¹,

Bridges²

1958

Plastic and Reconstructive Surgery

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Previous studies on the ontogeny of the specific immune response shortly after birth in several species (1-10) have indicated that newborn Chicks, guinea pigs, rabbits, and human beings form little or no detectable antibody in response to antigenic stimulation, but develop this ability between 2 and 4 weeks of age. In several known situations, however, such antigenic stimulation is not lost upon the newborn animal but results in a highly specific hiatus in his immunological capacity which persists after maturity. The studies establishing this last concept are reviewed exhaustively by Billingham, Brent, and Medawar (11) particularly in reference to "acquired tolerance" to homografts. In respect to less complex antigens, the investigations of Hanan and Oyama (12), Dixon andMaurer (I3), and Cinader and Dubert (14) have indicated that multiple injections of heterologous plasma proteins during the neonatal period result in prolonged and specific inability to respond immunologically to the injected protein.This investigation has been concerned with the mechanisms which govern the early development of specific immunity in mammals and particularly the unresponsive state resulting from neonatal exposure to antigen, The present paper describes the production of a prolonged state of immunological unresponsiveness in rabbits by a single injection of defined protein antigens at birth, and defines the amount of antigen required, the duration of the unresponsive state, the degradation of antigen in unresponsive animals, and also describes a number of attempts to produce an analogous state with a variety of bacterial antigens. A preliminary report of these studies has appeared else-*

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Section: Discussionmentioning

confidence: 82%

Immunological unresponsiveness in rabbits produced by neonatal injection of defined antigens

Smith¹,

Bridges²

1958

Plastic and Reconstructive Surgery

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“…Leaving the problem of deaths among the recipients aside for the moment, it is clear that there is considerable variability among different donor/recipient strain combinations in the proportion of mice rendered tolerant by neonatal injection, a point which has also been noted by other workers (Martinez, Smith, Aust & Good 1958). The reasons for this variability must include differences in the immunological status of newborn mice of various strains, and differences in the degree of genetic dissimilarity (particularly at the H-2 locus-see Snell, 1953Snell, , 1957Gorer, 1956) between donor and recipient strains.…”

Section: Discussion a N D Conclusion 6t Induction Of Tolerance In Micementioning

confidence: 58%

“…The question of whether a lasting tolerance of homologous tissues depends upon the persistence in the hosts of donor strain cells must for the time being remain unanswered. There can now be no doubt at all that the systemic inoculation of newborn mice with homologous cell suspensions leads to the formation of cellular chimeras, the injected cells surviving and almost certainly proliferating in many host organs ( §3 -8 ; Billingham & Brent 1957; see also Martinez, Smith, Aust, Mariani & Good 1958). But it would be premature to conclude that because donor strain cells are present in the tolerant animal the state of tolerance (once induced) could not continue without them.…”

Section: Discussion a N D Conclusion 6t Induction Of Tolerance In Micementioning

confidence: 99%

Quantitative studies on tissue transplantation immunity IV. Induction of tolerance in newborn mice and studies on the phenomenon of runt disease

Billingham

Brent

1959

Phil. Trans. R. Soc. Lond. B

239

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A simple method for the induction of actively acquired tolerance of homologous tissues in newborn mice is described (§§2-1, 2-2 and 2-3). With some donor/recipient strain combinations a high proportion of mice injected intravenously with homologous tissue cells is rendered tolerant of skin grafts from animals of the donor strain (§§3-1, 3-4 and 3-5), provided that the cells are administered within 24 h of birth. As the age of the recipients increases, so the proportion of tolerant mice falls (§3-2); a ‘ eutral period’ in the life of the recipients lies between the latest age at which they can be rendered tolerant and the earliest age at which they can be rendered immune. The induction of tolerance is less effective when homologous cells are injected intraperitoneally into newborn mice, and (with our strains) wholly ineffective when they are injected subcutaneously (§3-3). Tolerance can be induced with spleen, bone marrow or thymus cells (§3-4), and abolished (‘adoptive immunization’) with sensitized spleen and thymus cells as well as with lymph node cells (§5-2). Further experiments on the specificity of tolerance are described (§5.1). In newborn rabbits, the intravenous inoculation of homologous spleen or thymus cells results in the induction of tolerance in only a small proportion of animals (§3-6). The injection of adult homologous lymphoid cells into newborn mice leads to the development of a syndrome described as runt disease because, in its extreme form, it is characterized by gross retardation in development (§3-5). Runt disease is marked by varying degrees of involution of the recipients’ lymph nodes, and by pathological changes in the spleen, liver and other organs (§3-7). In its acute form it is fatal, but when more mildly expressed it need not be a serious handicap (§3-5). Two possible causes of runt disease are considered and subjected to experimental test (§4). The theory that runt disease is infective in origin cannot be upheld (§4.1). O n the contrary, it is shown conclusively that runt disease is immunological in origin, and that it is the consequence of an immunological reaction of the homologous cells against the tissues of their hosts (§6-2). For (a) the injected homologous cells persist indefinitely in the tissues of their hosts (§3-8); (b) although the injection of Fxhybrid spleen cells into newborn mice of the parental strains is usually quite harm less (§4-3), the injection of parental strain cells into hybrid recipients is followed by the typical syndrome of runt disease (§4-6); (c) mice can be protected from runt disease if they receive, together with the homologous cells, adult isologous spleen cells (§4-4); (d) the severity and frequency of runt disease are enhanced if sensitized homologous spleen cells are injected—i.e. cells from donors already sensitized by host strain tissues (§4-5); (e) acute runt disease can be avoided by the injection of adult tissue cells containing no, or only a very small proportion of, immunologically competent cells (§§4-2, 6-3); and (f) the severity and incidence of runt disease are largely determined by antigenic differences between donor and host strains (§6-2). Finally (g) it is already known that embryonic cells, though adept in producing tolerance, fail altogether to produce runt disease (§6-3). Tolerance of homologous tissues can occur in the complete absence of runt disease and cannot therefore depend upon the lymphoid hypoplasia that accompanies it (§6-3). O n the other hand, runt disease frequently depends upon the induction of tolerance by the injected cells, which are therefore able to persist and to react against the tissues of the host over a relatively long period of time. W ith certain donor/recipient strain combinations in which runt disease is particularly violent and rapid in onset, the induction of complete tolerance need not be necessary (§6-3), the young hosts succumbing to the disease before their own defence mechanism has m atured sufficiently to destroy the cells that cause it. W ith some donor/recipient strain combinations, the susceptibility to runt disease of hybrid mice injected with spleen cells from mice of the parental strains falls off with increasing age (§ 4-6), despite the fact that with this experimental design even adult recipients may be expected to be ‘ tolerant ’ of the injected cells. Similarly, the injection of adult mice made tolerant at birth with large doses of donor strain spleen cells does not bring about an increase in the severity of the disease (§4‘7). The production of runt disease in a severe form seems therefore to depend upon the hosts’ own lymphoid organs being relatively undeveloped when confronted with foreign lymphoid cells. It has been shown by Simonsen that the splenomegaly produced in chickens injected in ovo or soon after hatching with homologous spleen or blood cells is due to a ‘ graft-against-host ’ reaction (§6*2), and the same interpretation has been put upon the ‘secondary disease’ which often occurs in irradiated mice protected against the effects of radiation by adult homologous spleen or bone marrow cells (§6-4). These two phenomena and runt disease are therefore considered to have a common etiology. The occurrence of runt disease is a sensitive indicator of the presence of immunologically competent cells in the inocula used to induce tolerance. The finding that blood leucocytes and thymus cells can cause runt disease when injected into newborn mice (§4-2) suggests that at least some of the cells among them are capable of immunological reactivity. Bone marrow cells, whilst bringing about some degree of lymphoid hypoplasia, do not cause acute runt disease, and they may therefore be used conveniently for the induction of tolerance with those donor/recipient strain combinations in which the injection of spleen cells is always lethal. Certain clinical implications are discussed (§6-5). It is suggested that the possibility of ‘graft-against-host’ reactions and the occurrence of immunologically competent cells in adult blood should be borne in mind in the interpretation of haemolytic disease and in devising treatments of any kind which depend upon the transplantation of lymphoid cells.

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