Willys K. Silvers

Quantitative studies on the induction of tolerance of homologous tissues and on runt disease in the rat.

The principle that rats may be rendered tolerant of homologous tissue grafts following preor early postnatal exposure to living homologous cells is now well established (Woodruff and Simpson, 1955; Billingham et al., 1956; Lengerovh, 1957; Egdahl et al., 1958). It is also known that “runt” disease (Billingham, 1958; Billingham and Brent, 1959) not infrequently occurs in this animal, as in the mouse, if the inoculum employed to induce tolerance contains a high proportion of immunologically competent cells (Woodruff and Sparrow, 1957; Egdahl et al., 1958; Billingham and Silvers, 1959~). Their size renders rats much more convenient subjects than mice for detailed analyses of quantitative aspects of the induction of tolerance and the pathogenesis of runt disease: for example, large amounts of bone marrow can be obtained from a single animal, thoracic ducts of rats can be cannulated to obtain almost pure lymphocytes in considerable quantities, and daily samples of blood may be taken from very young animals for exact hematological analyses without prejudicing their well-being. Unfortunately, however, these advantages hitherto have been more than counterbalanced by the lack of the necessary isogenic strains, so that present knowledge derives largely from work conducted on mice. The recent availability of 2 highly inbred strains of rat, the Lewis (albino phenotype) and the B.N. (chocolate), differing so widely with respect to their origins that the degree of genetic disparity between them is likely to be very great (Billingham and Silvers, 19593), has terminated this unsatisfactory state of affairs and thus facilitated the investigations that form the subject matter of this paper. Destruction of skin homografts exchanged between adult members of the B.N. and Lewis strains is invariably complete within 13 days, and the median survival time (MST) of Lewis

THE NEOGENESIS OF SKIN IN THE ANTLERS OF DEER

To most biologists it is almost if not quite axiomatic that adult mammals cannot regenerate normal skin in areas where its entire thickness has been lost or destroyed. The very existence of a specialized branch of surgery that deals largely with the making good of cutaneous lesions is testimony of the incompetence of man to generate new skin. The natural healing of a wound involving the loss of the full thickness of the skin is the result of two more or less concomitant processes. First, the loss of the substance of the corium is made good by the formation of highly vascular granulation tissue that is progressively resurfaced by epithelium of migratory origin from the wound margins. Second, as a result of tensile forces generated within the wound area itself, and almost certainly within the substance of the granulation tissue or its derivatives, the normal skin from the original wound margins becomes drawn inward, and there is a consequent reduction in the extent of the lesion (Billingham and Medawar, 1955; Abercrombie et al., 1956; Billingham and Russell, 1956a; Watts et al., 1958). In regions of the body where the skin is loosely knit to the underlying structures and is therefore freely mobile, as in the trunk of nearly all mammals, contracture usually brings about complete closure of the wound by apposition of its original edges, so that only a narrow scar remains. The loss of skin substance that this process entails is gradually made good by a compensatory expansion of the surrounding skin by a process of intussusceptive growth-that is, the formation of new tissue upon or within the framework provided by pre-existing tissue (Billingham and Medawar, 1955 ; James, 1959). However, in areas of the body where the skin is firmly attached to the underlying tissues (as in the skin over most of the body of man and in the skin covering the ear cartilage of most animals) contracture cannot proceed to completion. There is a permanent residual scar of variable extent, comprising tough, relatively inelastic, white fibrous tissue covered by epithelium. The formation of this stable scar cannot be regarded as a regeneration since nothing has been regenerated: scar tissue is certainly not true skin that has been formed anew. I t differs profoundly from normal skin with respect to the configuration of its dermoepidermal interface and its fibrous architecture. There is a deficiency of elastic fibers and a tendency for its collagen fibers to be disposed in a horizontal plane rather than in the usual three-dimensional packing. This is responsible for its poorly developed resilience. Hairs are not normally regenerated anew, although it is commonly said that regeneration of sweat glands may take place in scar tissue in man. * Some of the work reported in this paper was supported by Grant C-3577 from the National Cancer Institute, Public Health Service, Bethesda, Md. The Wistar Instilute, Philadelphia, Pa.

Transplantation Immunity of Gestational Origin in Infant Rats

Comparison of the survival times of homografts of BN skin on 3-day-old Lewis rats born of mothers of the same isogenic strain with those of BN grafts on infant Lewis hosts that had developed in an F1 (Lewis x BN) hybrid, gave no evidence of maternally induced tolerance as a result of development in an antigenically alien environment. On the contrary, the significantly shorter median survival time of the grafts on the hybrid-derived Lewis group suggests that sensitization had occurred as a consequence of natural exposure during gestation to small numbers of maternal cells.