Intrathymic Tolerance Induction: Determination of Tolerance to Class II Major Histocompatibility Complex Antigens in Maturing T Lymphocytes by a Bone Marrow‐Derived Non‐Lymphoid Thymus Cell

Abstract

Two new experimental approaches were established to analyse the influence of the thymus on tolerance induction to major histocompatibility complex (MHC) antigens: The aim of the first experiment was to perform successful transplantation of adult allogeneic thymus tissue into nude mice, an attempt that has been unsuccessful in the past. Tolerance for the MHC genotype of a prospective thymus graft recipient (A) was induced in mice of strain B by injection of (A X B) splenocytes during the neonatal period. Adult thymic tissue obtained from these allogeneic donors (B) were grafted into the nude mice of strain A. The allogeneic thymus was accepted by the nude mice and immunoreconstitution was achieved. Subsequently the recipients developed tolerance to the MHC antigens of the allogeneic thymus donor as proved by mixed lymphocyte cultures and the acceptance of skin grafts. The second experiment was designed to determine which Ia-positive thymic compartment participates in conferring tolerance to MHC antigens in maturing T lymphocytes. Chimaeric thymus grafts were created by transplantation of neonatal thymus (A) into allogeneic nude mice (B) for a period of 8 weeks. The graft was populated with host bone marrow-derived Ia antigen-positive cells. The chimaeric thymuses consisting of type A epithelium but populated with both type A and B lymphocytes and non-lymphoid cells (i.e. Ia-positive macrophages and dendritic cells), were newly transplanted into nude mice of strain A. The engraftment lead to immunological reconstitution and the nude mice acquired tolerance to the MHC antigens expressed by the allogeneic Ia-positive cells populating the chimaeric graft. Irradiation of the chimaeric thymus prior to transplantation allowed transplantation of chimaeric thymus devoid of living thymocytes but still populated with functionally intact Ia-positive non-lymphoid cells. Transplantation of irradiated chimaeric thymuses resulted in immunoreconstitution and induced exactly the same allotolerance pattern as described above. The results demonstrate that not thymus epithelial cells but a bone-marrow-derived non-lymphoid thymus cell, most likely the Ia-antigen-positive thymic macrophage of dendritic cell, is responsible for the induction of tolerance to MHC antigens in developing T lymphocytes.

Presence of donor-derived thymic epithelial cells in [B6→MRL/lpr] mice after allogeneic intra-bone marrow–bone marrow transplantation (IBM–BMT)

“…It should also be noted that the immunological tolerance to the host is induced in allogeneic BMT. Although the mechanism has not been elucidated, the mixed status of donor-and host-type TECs and DCs in the thymus may play a crucial role in the induction of tolerance to both donor-and host-type MHC determinants [44].…”

Mechanisms of Tolerance Induction by Hematopoietic Chimerism: The Immune Perspective

“…It is questioned what are the specific antigenic targets attacked in the process of rejection: tissue, major or minor MHC antigens? One proposition suggests that transplant tolerance is specific to donor class I and II MHC , endorsed by the capacity of hematopoietic chimerism to induce tolerance to a variety of donor‐matched tissue and organ grafts . The prevalent explanation of alloreactivity suggests that T cells responses to peptide‐MHC complexes are less peptide specific than T‐cell recognition of foreign MHC (also termed “degenerate” response) .…”

“…The observation that focused thymic irradiation substitutes and reduces the morbidity associated with high‐dose TBI led to the concept that the role of preparative conditioning is to reset thymic function . Tolerance by mixed chimerism is considered as a pure central clonal deletion mechanism mediated by both donor and host APC of bone marrow origin operating in the thymus to select clones reactive against reciprocally mismatched antigens . The evolving argument attributes a major role to continuous elaboration of APC to ensure negative selection of newly developed thymocytes, whereas peripheral chimerism and persistence of alloantigens are dispensable .…”

Novel primary thymic defect with T lymphocytes expressing gamma delta T cell receptor.

“…Only occasional small lymphocytes Geisler, Pallesen, Platz, 0dwn, Dickmeiss, Ryder, Svejgaard, Plesner, Larsen, Koch -6), control one (lanes 7-12), and control two (lanes [13][14][15][16][17][18]. Precipitations were performed with normal mouse serum as negative control (lanes 1, 2,7,8,13,14), monoclonal antibody (IF) (lanes 3, 4,9,10,15,16), and monoclonal antibody TCR-61 (lanes 5, 6,11,12,17,18). Samples were run under non-reducing (uneven numbered lanes) or reducing (even numbered lanes) conditions.…”