Islet-Specific CTL Cloned from a Type 1 Diabetes Patient Cause Beta-Cell Destruction after Engraftment into HLAA2 Transgenic NOD/SCID/IL2RG Null Mice

Despite increasing evidence that autoreactive CD8 T-cells are involved in both the initiation of type 1 diabetes (T1D) and the destruction of beta-cells, direct evidence for their destructive role in-vivo is lacking. To address a destructive role for autoreactive CD8 T-cells in human disease, we assessed the pathogenicity of a CD8 T-cell clone derived from a T1D donor and specific for an HLA-A2-restricted epitope of islet-specific glucose-6-phosphatase catalytic-subunit related protein (IGRP). HLA-A2/IGRP tetramer staining revealed a higher frequency of IGRP-specific CD8 T-cells in the peripheral blood of recent onset human individuals than of healthy donors. IGRP(265-273)-specific CD8 T-cells that were cloned from the peripheral blood of a recent onset T1D individual were shown to secrete IFNγ and Granzyme B after antigen-specific activation and lyse HLA-A2-expressing murine islets in-vitro. Lytic capacity was also demonstrated in-vivo by specific killing of peptide-pulsed target cells. Using the HLA-A2 NOD-scid IL2rγ(null) mouse model, HLA-A2-restricted IGRP-specific CD8 T-cells induced a destructive insulitis. Together, this is the first evidence that human HLA-restricted autoreactive CD8 T-cells target HLA-expressing beta-cells in-vivo, demonstrating the translational value of humanized mice to study mechanisms of disease and therapeutic intervention strategies

L3T4 and Lyt-2 T cells are both involved in the generation of low-dose streptozotocin-induced diabetes in mice.

In order to determine the role of different T lymphocyte subsets in the pathogenesis of low-dose streptozotocin (LD-Sz) induced diabetes, we treated mice with Sz together with repeated injections of rat monoclonal antibodies (MoAb) with specificity towards the mouse T cell differentiation markers L3T4 ('helper/inducer' T cells and some macrophages), Lyt-2 ('cytotoxic/suppressor' T cells and NK cells) and Thy-1 (pan T lymphocytes). Treatment depleted target cells in peripheral blood and spleen; decreased the ability of spleen cells to respond to mitogens; and, in the case of depletion of the L3T4 T cell subset, prevented a humoral immune response to SRBC. Treatment with MoAb against either of the two T cell subtypes could protect from hyperglycaemia and loss of body weight, suggesting that both T cell subsets were implicated in the development of LD-Sz induced diabetes. Immunocytochemical analysis of pancreatic sections showed that both L3T4+ and Lyt-2+ cells participated in islet infiltration together with macrophages. Treatment with MoAb markedly reduced islet infiltration by both L3T4+ and Lyt-2+ cells but not by macrophages. The suppressive effect of MoAb against either L3T4 or Lyt-2 on diabetes development suggests that the pathomechanism involved is different from that in experimental autoimmune neuritis and adjuvant arthritis where Lyt-2 cells are not involved

T cell tolerance induced by therapeutic antibodies

Ever since the discovery of Medawar, over 50 years ago, that immunological tolerance was an acquired phenomenon that could be manipulated in neonatal mice, the ability to induce therapeutic tolerance against autoantigens, allergens and organ grafts has been a major driving force in immunology. Within the last 20 years we have found that a brief treatment with monoclonal antibodies that block certain functional molecules on the surface of the T cell is able to reprogramme the established immune repertoire of the adult mouse, allowing indefinite acceptance of allografts or effective curing of autoimmune diseases. We are only now just beginning to define many of the regulatory mechanisms that induce and maintain the tolerant state with the aim of being able to safely and reliably apply these technologies to human clinical situations

Interleukin-21 Receptor-Mediated Signals Control Autoreactive T Cell Infiltration in Pancreatic Islets

Tumorimmunolog

Physikalisch-chemische Aspekte immunologischer und anderer reversibler Assoziations-Reaktionen

Peer Reviewe