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Biomedical subjects

R E Billingham

Publications and source records attributed to R E Billingham.

At least 91 records · Page 5Linked to original sources
PubMed1973

Maternally acquired runt disease.

Without altering the structural integrity of the placenta by irradiation or drugs, we have shown that it is possible to immunize females both adoptively and actively against the paternally inherited transplantation antigens of their fetuses. Such immunization causes a high incidence of runt disease among the litters. Although the putative chimeric status of the affected offspring has yet to be confirmed, the results of our experiments support the thesis that runt disease is caused by the activities of "unwanted" immigrant lymphocytes from the maternal circulation. Our results suggest that immunologically activated cells are more likely to cross the placenta than normal cells and that this greater mobility may not be related to the immunologic specificity of the activated cells. Two factors may have contributed to the apparent failure of numerous previous attempts to demonstrate the capacity of transplantation immunity to affect the well-being of a fetus or, more correctly, its placenta, in the way that might be expected of a homograft. (i) Investigators were preoccupied with obtaining a classic type of rejection, in utero, analogous to the rejection of an orthotopic skin homograft. The birth of consistently healthy-looking litters, interpreted as a failure of the experiment, convinced the investigators of the efficacy of nature's solution of the homograft problem and there was no reason for them to suspect its possible limitations. Observation of the litters for several weeks might have uncovered the phenomenon of maternally induced runt disease. (ii) Most investigators resorted to hyperimmunization of the mothers. This would have facilitated the synthesis of protective isoantibodies capable of interfering with the expression of the potentially harmful cellular immune response (6). Ever since the abnormalities of runt disease were first described they have repeatedly been compared to those observed in patients with certain lymphomas (17). Various theories have been propounded as to how maternally transmitted graft-versus-host reactivity might lead to the development of these tumors. In mice it has been established that graft-versus-host reactivity may result in a high incidence of lymphomas (18). Recent analysis indicates that this graft-versus-host reactivity unmasks and activates normally latent and undemonstrable oncogenic viruses (19). The work we describe in this article may have some relevance to the possible clinical significance of transplacental cellular mobility in man. We suggest that the relatively high incidence of lymphomas in children might also be, in part at least, due to unmasking of oncogenic viruses by subclinical graft-versus-host reactivity mediated by immunocompetent cells of maternal origin. The statistical evidence that male infants are at greater risk than females (20) is concordant with our observation that maternally induced runts include a significantly higher proportion of males than females (10).

Animals↗
PubMed1972

Studies on normal and immune lymphocyte transfer reactions in guinea pigs, with special reference to the cellular contribution of the host.

Using guinea pigs of strains 2 and 13 and their F(1) hybrids as experimental subjects, various lines of evidence have been obtained that in this species, as in all others tested, the only significant cellular antigens with which donor lymphocytes engage when normal and immune lymphocyte reactions are incited are radiosensitive leukocytes. Constitutive cells of the skin are unimportant. (a) The intensities of these reactions in irradiated subjects are dependent upon the peripheral leukocyte concentration. When this falls below a certain threshold no reactions are incitable. (b) Highly leukopenic animals are capable of developing immune lymphocyte transfer (ILT) reactions if normal lymphoid cells of their own genetic constitution are mixed with the putative attacking donor cells, as "supplementing antigen," before inoculation. (c) Radiation-chimeric strain 13 animals having F(1) hybrid leukocytes in their bloodstream give typical ILT reactions when challenged intradermally with strain 13 anti-2 node cells. Exposure of strain 2 animals to 600 R does not prevent their becoming actively immunized if, 24 hr later, they are injected intradermally with strain 13 lymphocytes. However, this sensitization, revealed by the host's capacity to give delayed hypersensitivity reactions, wanes as leukopenia progresses. On the basis of this and other findings it is argued that the flare-up stage of the NLT reaction in preirradiated hosts is mainly an expression of host sensitivity against the transferred alien cells. Two unexpected observations have been made in the course of this study: (a) F(1) hybrid animals developed what appeared to be a strong delayed hypersensitivity after intradermal inoculation with parental strain lymphoid cells or antigenic extracts prepared from them. (b) If strain 13 guinea pigs which had been sensitized against strain 2 tissue antigens by intradermal injection of lymphocytes 7 days beforehand were inoculated intravenously with strain 2 antigenic extract a significant proportion of the animals developed severe delayed necrotizing reactions, recall flares, at some or all of the healed skin inoculation sites.

Animals↗
PubMed1972

Further evidence concerning the autoantigenic status of the trophoblast.

Heterologous antisera were raised by inoculation of rabbits with fairly pure suspensions of trophoblast, lymphoid, fetal (excluding placental components), epidermal, decidual, and renal cells from Fischer rats. After absorption of hemagglutinins, these antisera were assayed for abortifacient activity by intramuscular inoculation into time-mated Fischer females. The anti-trophoblast serum aborted all the recipients, but had some nonspecific activity in that it caused the deaths of 12% of them. Anti-lymphocyte serum was more toxic and less potent as an abortifacient. None of the other sera harmed either the mothers or their fetuses. However, the anti-kidney cell serum caused kidney lesions. Absorption of the anti-trophoblast serum with lymphoid cells completely removed its toxicity for the pregnant females without perceptible impairment of its abortifacient activity. However, the latter could be removed by absorption with trophoblast cells. (a) The lymphocyte-absorbed anti-trophoblast serum was equally effective in aborting rats over the range 7-18 days postconception; (b) a single injection of 1 ml was sufficient in most cases, and (c) it was equally efficacious in terminating gestation in rats irrespective of their genetic constitution, and (d) its effect was highly species-specific. These findings support the premise that a unique antigen (or antigens), of possible clinical significance, is associated with trophoblast cells.

Abortion, Induced↗
PubMed1972

Maternally induced transplantation immunity, tolerance, and runt disease in rats.

A previous report that the offspring of outbred Sprague-Dawley rats, born of mothers presensitized or tolerant with respect to tissue antigens of the Lewis strain, and reinoculated with Lewis cells during their pregnancy, reject test grafts of Lewis skin in an accelerated manner has been confirmed. This "maternally induced" alteration in reactivity of the progeny has been found to be long lasting, immunologically specific, and probably not due to transfer of humoral antibody. It has been established that the reexposure of the mothers to donor cellular antigen during pregnancy augmented the influence of the prior states of tolerance or sensitivity. To obviate the complications inherent in working with the outbred Sprague-Dawley rats, the key experiments summarized above were repeated with isogenic Fischer rats as parents and Lewis rats as the tissue donors as before. With this combination it was found that a state of prior sensitization or tolerance in the mothers resulted in the apparent induction of tolerance in some of their progeny. Reinoculation of either the tolerant or sensitized mothers during pregnancy slightly increased the incidence and degree of impairment of their offsprings' capacity to reject Lewis skin grafts. A single intraperitoneal injection of 100 x 10(6) million Lewis lymphoid cells into normal Fischer rats in the 14th-16th day of pregnancy also weakened the reactivity of their progeny to Lewis test grafts. Further to test the premise that this weakened reactivity might be due to maternal induction of tolerance, by antenatal transmission of alien cells, the lymphohematopoietic tissue system of adult Fischer females was replaced by that from Lewis donors with the aid of cyclophosphamide. It was anticipated that when these animals were mated with Fischer males, sufficient Lewis leukocytes might cross the placentas to induce high degrees of tolerance. Although normal sized healthy litters were born, about 50% of the infants succumbed to graft-versus-host (GVH) or runt disease within 40 days, many of them giving evidence of being tolerant of Lewis grafts. The mothers, too, developed chronic GVH disease. The offspring of Fischer females made chimeric with cells from (Fischer x Lewis)F(1) hybrid donors, as well as their mothers, remained healthy. Intraperitoneal injection of normal Fischer females, in the 15th-17th day of pregnancy, with 100 million lymphoid cells from specifically sensitized Lewis rats, also caused fatal runt disease to develop in about 50% of their offspring, but left the mothers unscathed. Taken together, these various findings indicate that in some genetic contexts at least the extent of the natural surreptitious transplacental cellular traffic can be considerably augmented experimentally, though how this comes about and why lymphocytic cells that are foreign to the mother can apparently gain access to fetuses more readily than her own cells remain to be determined.

Animals↗
PubMed1971

The lymphatic status of hamster cheek pouch tissue in relation to its properties as a graft and as a graft site.

Hamster cheek pouch skin, transplanted to the side of an isogenic host's chest wall, retains its immunologically privileged status as evidenced by the prolonged survival of inlaid homografts of ordinary skin. Various findings sustain the premise that exemption from rejection by otherwise susceptible homografts in both intact pouch tissue and in established pouch skin isografts is due to an impediment in the afferent pathway of the immunologic reflex, i.e., to deficient lymphatic drainage. Although lymphatics were not apparent when dye was injected into pouch skin grafts or into grafts of ordinary skin sustained by them, lymph vessels were readily and consistently revealed by dye injected into intact trunk skin or established isografts of trunk skin. When suspensions of viable lymph node cells from specifically sensitized parental strain donors were injected superficially into either the intact skin or established grafts of normal skin on F(1) hybrid hamsters, a striking hypertrophy of the regional lymph nodes occurred, due to graft-versus-host reactivity. However, similar cell suspensions inoculated into intact pouch tissue or into pouch skin grafts on F(1) hamsters incited no regional lymphadenopathy, indicating the lack of appropriate pathways to the nodes. When skin homografts were inlaid eccentrically into pouch skin isografts, so that they were in contact with host skin at one edge, rejection occurred. Furthermore, rejection of long-established intrapouch skin homografts resulted if the hosts received: (a) small homografts of ordinary skin transplanted to conventional beds; (b) suspensions of donor strain pouch skin epidermal cells, injected intracutaneously; (c) lymph node cells from specifically sensitized donors of the same strain, i.e. adoptive immunization; or, (d) if a portion of the target homograft's perimeter was surgically approximated to body skin. Treatment of normal hamsters with two closely spaced pulses of ALS, although only marginally effective in prolonging the lives of homografts of trunk skin, enabled pouch skin homografts to survive for very long periods. The influence of this brief treatment with immunosuppressant was still demonstrable if challenge of hosts with the weakly immunogenic pouch skin homografts was delayed for 100 days.

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