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

Abstract

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.

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

“…If true, mixed chimerism could be a solution for both solid organ transplantation and cellular transplants, such as allogeneic islets used to treat type-1 diabetes. However, studies in full chimeras, where virtually all hematopoietic cells in the recipient are of donor origin, indicated that chimerism did not always allow acceptance of donor skin grafts; the recipients could show split tolerance [8][9][10]. Rejection of donor skin grafts in full chimeras suggested that in fact the chimeras were 'autoimmune', as donor T cells rejected the donor skin [11].…”

Synergy Among Lymphoid Cells Mediating the Graft-Versus-Host Response

“…In the mouse this reaction is characterized by loss of body weight, splenomegaly, hepatomegaly, lymph node atrophy, and death (3). Splenomegaly, an early and constant finding, forms the basis of the spleen weight assay developed by Simonsen to measure the vigor of the GVH reaction in recipient mice (4).…”

The French heritage in clinical kidney transplantation

“…Burnet and Fenner 25 predicted that such chimerism and thc ability to exchange other tissues could be induced by the kind of experiment eventually performed with Medawar by Billingham and Brent whosc definition of tolerance was that it "is due to a primary central failure of the mechanism of the immunological reaction, and not to some intercession, at a peripherallevel." 23 The surgical interest generated by thc dcmonstration that tolerance could be acquired was quickly dampened whcn it was learned by Billingham and Brent 26 with further experiments in mice that the penalty for the prophylactic infusion of such donor cells could be lethal graft-versus-host disease (GVHD). Many of the inoculated mice failed to thrive ("runt disease") and had skin erosions, hair loss, diarrhea, diffuse pneumonitis, and characteristic changes in their lymphoid organs.…”