IFN-γ production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo

The significance of cytokine production by CD4+ regulatory T (T reg) cells after antigen exposure in vivo and its impact on their regulatory activity remains unclear. Pretreatment with donor alloantigen under the cover of anti-CD4 therapy generates alloantigen reactive T reg cells that can prevent rejection of donor-specific skin grafts that are mediated by naive CD45RBhighCD4+ T cells. To examine the kinetics and importance of cytokine gene transcription by such alloantigen-reactive T reg cells, pretreated mice were rechallenged with donor alloantigen in vivo. CD25+CD4+ T cells, but not CD25−CD4+ T cells, showed a fivefold increase in IFN-γ mRNA expression within 24 h of reencountering alloantigen in vivo. This expression kinetic was highly antigen-specific and was of functional significance. Neutralizing IFN-γ at the time of cotransfer of alloantigen reactive T reg cells, together with CD45RBhighCD4+ effector T cells into Rag−/− skin graft recipients, resulted in skin graft necrosis in all recipients; the generation and function of alloantigen-reactive T reg cells was impaired dramatically in IFN-γ–deficient mice. These data support a unique role for IFN-γ in the functional activity of alloantigen-reactive T reg cells during the development of operational tolerance to donor alloantigens in vivo

The role of CD4+CD25+ regulatory T cells in a mouse transplantation tolerance model

Clinical transplantation continues to rely on the use of non-specific immunosuppressive therapy, which reduces the incidence of graft rejection but also carries with it undesirable side effects such as infection and malignancy. A preferable option would be to induce operational graft tolerance without the need for such non-specific therapy, for example by harnessing natural mechanisms. In recent years there has been much progress in the characterisation of CD4+ cells that possess suppressive or regulatory properties in experimental systems; particular attention has been focussed upon CD4+ cells expressing CD25, the α subunit of the IL-2 receptor, which have been shown to possess regulatory capacity both in vitro and in vivo in autoimmune disease and transplantation models. The aim of this study was to examine the potential role of CD4+CD25+ regulatory T cells (Treg) in the induction phase of tolerance in a transplantation model. Pre-treatment of mice with fully allogeneic blood administered under the cover of anti-CD4 antibody is shown to lead to the generation of CD4+CD25+ cells capable of preventing the rejection of donor type, but not third party, skin allografts mediated by CD4+CD45RBhigh cells in secondary recipients. In addition to their suppressive properties in vivo, these CD4+CD25+ cells also display the ability to regulate the proliferation of target T cell populations in vitro. Generation of CD4+CD25+ Treg by the pre-treatment protocol is not reliant upon an intrathymic selection process nor upon the expansion of a pre-existing CD4+CD25+ Treg population, but can occur through the conversion of peripheral CD4+CD25- cells to a regulatory phenotype. Although the regulatory function of the CD4+CD25+ cells generated by pre-treatment is donor strain-specific in vivo, this specificity can be overcome by activating the cells before their regulatory capacity is tested. Moreover, CD4+CD25+ cells generated by pre-treatment with a non-cellular protein antigen completely unrelated to the graft can also regulate skin allograft rejection provided that these Treg are first activated. It is hoped that the principles defined by these findings identify a strategy that may be applicable in clinical transplantation and in the therapy of autoimmune disease

The role of CD4+CD25+ regulatory T cells in a mouse transplantation tolerance model

Clinical transplantation continues to rely on the use of non-specific immunosuppressive therapy, which reduces the incidence of graft rejection but also carries with it undesirable side effects such as infection and malignancy. A preferable option would be to induce operational graft tolerance without the need for such non-specific therapy, for example by harnessing natural mechanisms. In recent years there has been much progress in the characterisation of CD4+ cells that possess suppressive or regulatory properties in experimental systems; particular attention has been focussed upon CD4+ cells expressing CD25, the α subunit of the IL-2 receptor, which have been shown to possess regulatory capacity both in vitro and in vivo in autoimmune disease and transplantation models. The aim of this study was to examine the potential role of CD4+CD25+ regulatory T cells (Treg) in the induction phase of tolerance in a transplantation model. Pre-treatment of mice with fully allogeneic blood administered under the cover of anti-CD4 antibody is shown to lead to the generation of CD4+CD25+ cells capable of preventing the rejection of donor type, but not third party, skin allografts mediated by CD4+CD45RBhigh cells in secondary recipients. In addition to their suppressive properties in vivo, these CD4+CD25+ cells also display the ability to regulate the proliferation of target T cell populations in vitro. Generation of CD4+CD25+ Treg by the pre-treatment protocol is not reliant upon an intrathymic selection process nor upon the expansion of a pre-existing CD4+CD25+ Treg population, but can occur through the conversion of peripheral CD4+CD25- cells to a regulatory phenotype. Although the regulatory function of the CD4+CD25+ cells generated by pre-treatment is donor strain-specific in vivo, this specificity can be overcome by activating the cells before their regulatory capacity is tested. Moreover, CD4+CD25+ cells generated by pre-treatment with a non-cellular protein antigen completely unrelated to the graft can also regulate skin allograft rejection provided that these Treg are first activated. It is hoped that the principles defined by these findings identify a strategy that may be applicable in clinical transplantation and in the therapy of autoimmune disease.</p

The role of CD4+CD25+ regulatory T cells in a mouse transplantation tolerance model

Clinical transplantation continues to rely on the use of non-specific immunosuppressive therapy, which reduces the incidence of graft rejection but also carries with it undesirable side effects such as infection and malignancy. A preferable option would be to induce operational graft tolerance without the need for such non-specific therapy, for example by harnessing natural mechanisms. In recent years there has been much progress in the characterisation of CD4+ cells that possess suppressive or regulatory properties in experimental systems; particular attention has been focussed upon CD4+ cells expressing CD25, the α subunit of the IL-2 receptor, which have been shown to possess regulatory capacity both in vitro and in vivo in autoimmune disease and transplantation models. The aim of this study was to examine the potential role of CD4+CD25+ regulatory T cells (Treg) in the induction phase of tolerance in a transplantation model. Pre-treatment of mice with fully allogeneic blood administered under the cover of anti-CD4 antibody is shown to lead to the generation of CD4+CD25+ cells capable of preventing the rejection of donor type, but not third party, skin allografts mediated by CD4+CD45RBhigh cells in secondary recipients. In addition to their suppressive properties in vivo, these CD4+CD25+ cells also display the ability to regulate the proliferation of target T cell populations in vitro. Generation of CD4+CD25+ Treg by the pre-treatment protocol is not reliant upon an intrathymic selection process nor upon the expansion of a pre-existing CD4+CD25+ Treg population, but can occur through the conversion of peripheral CD4+CD25- cells to a regulatory phenotype. Although the regulatory function of the CD4+CD25+ cells generated by pre-treatment is donor strain-specific in vivo, this specificity can be overcome by activating the cells before their regulatory capacity is tested. Moreover, CD4+CD25+ cells generated by pre-treatment with a non-cellular protein antigen completely unrelated to the graft can also regulate skin allograft rejection provided that these Treg are first activated. It is hoped that the principles defined by these findings identify a strategy that may be applicable in clinical transplantation and in the therapy of autoimmune disease.</p

Multiple Faces of Chronic Lymphocytic Leukaemia: A Patient with Renal, Cardiac, and Skeletal Complications

We describe a patient who had chronic lymphocytic leukaemia (CLL) Binet stage A at presentation with further evidence of disease at multiple sites but who initially required no treatment. However, several years later, her peripheral blood lymphocyte count started to increase, and soon after that she suffered an acute myocardial infarct (in the absence of coronary atheroma) together with proteinuric renal failure due to membranoproliferative glomerulonephritis. Her renal function improved markedly following anti-CLL chemotherapy. We postulate that her cardiac and renal disease were both complications of her CLL. In patients with CLL who develop new clinical signs or symptoms (even if apparently unrelated), consideration should be given as to whether these may be disease complications as this may serve as an indication to commence anti-CLL therapy; close liaison between different specialties is vital