Bruce Roser

Cellular Mechanisms in Neonatal and Adult Tolerance

Since Billingham et al. (1953) first showed that tolerance of foreign tissue grafts could be induced in mice before birth, it has been assumed that the mechanism of this form of tolerance was the same as self tolerance. More recently it has become clear that a watershed event in the development of the immune system separates neonatal tolerance and self tolerance. This is the expression of the Tcell receptor in the thymus and the peripheralization of the T-cell repertoire. This event, which begins on about day 16-17 in the mouse or rat embryo (Owen et al. 1986), defmes the onset of immune competence in the T-cell pool. Antigens injected at about the time of birth, on d 21, are injected into an animal which already has functional T cells. Antigens present before this time, whether normal self antigens or introduced foreign antigens, e.g. transgenic molecules, pre-date the expression of T-cell competence. If these antigens are expressed in the thymus they can clearly influence the fate of T cells at the point where the first nascent a/p T-cell antigen receptors are being expressed at the cell surface.

The Cellular Basis of Transplantation Tolerance in the Rat

Since the seminal paper of Billingham et al. (1953) on acquired tolerance to antigens of the Major Histocompatibility Complex (MHC), it has become increasingly clear that the permanent acceptance of skin allografts can reflect a spectrum of underlying immunological mechanisms. These range from antibody mediated enhancement to complete tolerance. The latter can be unambiguously defined as complete specific non-reactivity of the lymphoid cells of tolerant donors in all assays (in vivo and in vitro) for alloimmune function. Although complete tolerance may be induced in both neonatal and adult animals by a variety of procedures, the injection of F, hybrid bone marrow cells into the circulation of newborn parental animals is the classical technique and may be the least complex to analyze. It was towards an understanding of the cellular mechanisms underlying tolerance induced in this way that the following studies were directed.

T Cell leukaemia in the rat: the pathophysiology

Summary A new transplantable lymphocytic leukaemia of the inbred Hooded Oxford strain of rat is described. Fewer than 10 cells will transfer disease to syngeneic recipients. Leukaemic cells bear the surface markers of thymus‐derived (T) cells and recirculate from blood to lymph. In contrast to the usual thymic lymphomas of rodents the pathophysiology of the disease‐bears a close resemblance to human acute lymphoblastic leukaemia.

A Quantitative Study Of The Membrane Antigens On Leukaemic and Normal T Cells In The Pvg Rat

&NA; Membrane antigens on PVG leukaemic cells have been compared with those on normal PVG peripheral T cells by studying the capacity of the cells to bind antibodies against these cell types. The antibody bound has been quantitated by secondary binding of a radiolabeled anti‐immunoglobulin. It was shown that the leukaemic cell lacks the peripheral thymus‐derived lymphocyte antigens which the normal PVG peripheral T lymphocyte carries. In this respect, in its reduced distribution of the W3/13 antigen compared with T cells, as revealed by binding of the hybridoma monoclonal antibody W3/13, and in its abundance of Thy 1.1 antigen, the leukaemic cell resembles the immature thymocyte, rather than the mature T lymphocyte. This antigenic profile represents an illustration of de‐differentiation of tumour cells at the molecular level. Two antigens shared by PVG leukaemic cells, normal PVG peripheral T cells and thymocytes were indicated by absorption studies with antisera against the leukaemic cell. In an immunotherapy model, treatment with AUG cells sensitized against the PVG leukaemiacell resulted in elimination of leukaemiccellsfrom PVG rats. The peripheral T cell antigens clearly cannot be antigen(s) recognized by the AUG rat on the leukaemic cell, since the present studies indicate the absence of peripheral T cell antigens on this cell.

T cell leukaemia in the rat: stable marker chromosome in leukaemic cells

Summary The karyotype of a transplantable T cell leukaemia which arose originally in a PVG strain rat undergoing chronic internal β irradiation of the spleen was examined and a marker chromosome was found. Although the leukaemia progressively became more acute during 4 years of continuous passage the marker did not change. Cytogenetic analysis of normal rats given an acute exposure to external irradiation revealed, among other abnormalities, a marker of the same morphology; indicating that the original marker was probably radiation induced. This is the first description of a stable marker chromosome in an experimental animal leukaemia.