Cellular immunotolerance in the transplant.

In humans, a state of operational tolerance has been observed in some recipients who anecdotally or experimentally abandoned their immunosuppressive treatment. Besides, advances in the understanding of the immune response and the continuous appearance of new biological molecules have boosted the growing interest in transferring the knowledge concerning immune tolerance from experimental models to clinical transplantation. Most of the strategies for inducing tolerance target the T-lymphocytes, especially T CD4(+) since they play a central role in the regulation of the immune response. However, an effective tolerogenic treatment must also take into account the role of alloantibody producing B-lymphocytes, which have been shown to play a fundamental role in chronic rejection phenomena. There are multiple regulation and silencing mechanisms that operate both during lymphocyte ontogeny in the bone marrow and thymus (central tolerance) and in the periphery (peripheral tolerance). These regulatory mechanisms include the destruction of APCs by cytotoxic lymphocytes, suppressive cytokines, and activation-induced cell death, among others. However, the mechanism that in recent years has come to be attributed the greatest role has been the active suppression of the response by T-lymphocytes themselves. These lymphocytes are named as regulatory T cells that include Tregs CD4(+)CD25(+), Tr1 cells and Th3. The great therapeutic potential of regulatory lymphocyte populations for the control of allogeneic rejection is evident and several clinical trials in humans have been started to be implemented using populations of both Tregs and Tr1 cells for the prevention of allogeneic reactions.

E2F1-/- C57BL/6 mice overexpressing a human Bcl-2 transgene in B cells develop a mild autoimmune syndrome.

Bcl-2, besides having an anti-apoptotic function, delays cell cycle progression at G1 to S. Overexpression of Bcl-2 in B cells induces an autoimmune syndrome (AIS) in pro-autoimmune genetic backgrounds. E2F1, a member of the E2F transcription factors, controls cell cycle, but it also induces cell death. E2F1(-/-) mice show an altered negative thymic selection but a conserved peripheral tolerance. As a consequence, these mice do not develop autoimmunity. Our aim was to evaluate whether deregulation of both apoptosis and cell cycle alters the mechanisms of tolerance and induces an AIS. C57BL/6 E2F1(-/-) mice were crossed with C57BL/6 mice overexpressing a human Bcl-2 transgene in B cells to obtain E2F1(-/-) hbcl-2 Tg mice. These mice were followed for up to 15 months of age with bleedings every three months to obtain serum and whole blood. The production of an AIS was assessed by quantitation of serum anti-DNA antibodies, renal light microscopy, and direct immunofluorescence in search of immunoglobulin deposits. E2F1(-/-) hbcl-2 Tg mice developed an AIS characterized by anti-DNA autoantibody production with renal damage observed after the 9th month of age. The lesions consisted mainly on cellular proliferation and mesangial deposits, compatible with a mesangial glomerulonephritis. The composition of deposits was predominantly of IgA, followed by IgM and IgG. Despite the development of renal damage, the AIS observed did not induce an accelerated mortality. The coexistence of an altered B cell apoptosis, together with the lack of E2F1, induces a mild AIS in the non-autoimmune background of C57BL/6 mice.