Papers by Stephen Cobbold
Faculty of 1000 evaluation for Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways
F1000 - Post-publication peer review of the biomedical literature, 2010
Suppression of Low-Dose Streptozotocin-Induced Diabetes in Mice by Monoclonal-Antibodies to Lymphocyte-T Subsets
Diabetologia, 1986
The effect of immunomodulatory lectins on diabetes development following low-dose streptozotocin ... more The effect of immunomodulatory lectins on diabetes development following low-dose streptozotocin treatment in inbred mice was studied. All lectins administered had been shown previously to suppress immune reactivity. Among plant lectins concanavalin A but not Lens culinaris or wheat germ agglutinin partially suppressed hyperglycaemia following low-dose streptozotocin. A similar inhibitory effect was found for the staphylococcal enterotoxin B. Finally, administration of an immunomodulatory lectin from vertebrates, electrolectin, also had a beneficial effect on the course of the disease. These findings indicate that some lectins have a suppressive effect on Type 1 diabetes in an animal model.
How may immunosuppression lead to tolerance? The war analogy
We wished to determine whether CD4 ؉ T cells could reject a skin graft that was discordant for a ... more We wished to determine whether CD4 ؉ T cells could reject a skin graft that was discordant for a single minor transplantation Ag in the absence of CD8 ؉ T cells or Ab. Transgenic A1(M) mice were constructed that express the rearranged V8.2 and V␣10 TCR genes from a T cell clone that is specific for the male Ag (H-Y) in the context of H2-E k. In addition, the RAG-1 ؊/؊ background was bred onto these mice to eliminate any endogenous TCR rearrangements. As expected, clonal deletion was found to be complete in the thymus of male A1(M)؋RAG-1 ؊/؊ mice, while only CD4 ؉ T cells were positively selected and found in the periphery of females. Female A1(M)؋RAG-1 ؊/؊ mice were able to rapidly reject (in <14 days) male (but not female) skin grafts in a CD4dependent fashion. After multiple grafts, it was confirmed that no CD8 ؉ T cells or surface Ig ؉ B cells were present. An immunofluorescent analysis of spleen cells after grafting showed that the majority of T cells expressed activation markers (CD44, CD25, and intracytoplasmic IL-2) and a significant proportion were making IFN-␥ and IL-4. Surprisingly, the transfer of either Th1 or Th2 CD4 ؉ T cell lines from these mice into T cell-depleted recipients was sufficient to cause a specific rejection of male skin.
Frontiers in Immunology, 2019
Lipid metabolism plays a key role in many cellular processes. We show here that regulatory T cell... more Lipid metabolism plays a key role in many cellular processes. We show here that regulatory T cells have enhanced lipid storage within subcellular lipid droplets (LD). They also express elevated amounts of both isoforms of diacylglycerol acyl transferase (DGAT1 & 2), enzymes required for the terminal step of triacylglycerol synthesis. In regulatory T-cells (Tregs), the conversion of diacylglycerols to triacylglycerols serves two additional purposes other than lipid storage. First, we demonstrate that it protects T cells from the toxic effects of saturated long chain fatty acids. Second, we show that Triglyceride formation is essential for limiting activation of protein kinase C via free diacyl glycerol moieties. Inhibition of DGAT1 resulted in elevated active PKC and nuclear NFKB, as well as impaired Foxp3 induction in response to TGFβ. Thus, Tregs utilize a positive feedback mechanism to promote sustained expression of Foxp3 associated with control of LD formation.
F1000 - Post-publication peer review of the biomedical literature, 2007
The study of T regulatory cells (T reg cells) has been limited by the lack of specifi c surface m... more The study of T regulatory cells (T reg cells) has been limited by the lack of specifi c surface markers and an inability to defi ne mechanisms of suppression. We show that the expression of CD39/ENTPD1 in concert with CD73/ecto-5′-nucleotidase distinguishes CD4 + /CD25 + / Foxp3 + T reg cells from other T cells. These ectoenzymes generate pericellular adenosine from extracellular nucleotides. The coordinated expression of CD39/CD73 on T reg cells and the adenosine A2A receptor on activated T effector cells generates immunosuppressive loops, indicating roles in the inhibitory function of T reg cells. Consequently, T reg cells from Cd39-null mice show impaired suppressive properties in vitro and fail to block allograft rejection in vivo. We conclude that CD39 and CD73 are surface markers of T reg cells that impart a specifi c biochemical signature characterized by adenosine generation that has functional relevance for cellular immunoregulation.
Rat Monoclonal-Antibodies to Prevent G-VS-H and H-VS-G Reactions in Bone-Marrow Transplantation
McAbs of Therapeutic Potential Which Interact with Host Effector Systems
Metabolic aspects underlying immune regulation
Rat Monoclonal Antibodies for Bone Marrow Transplantation — The Campath Series
Microenvironments in the Lymphoid System, 1985
1. Adv Exp Med Biol. 1985;186:869-75. Rat monoclonal antibodies for bone marrow transplantation--... more 1. Adv Exp Med Biol. 1985;186:869-75. Rat monoclonal antibodies for bone marrow transplantation--the CAMPATH series. Waldmann H, Cobbold S, Wilson A, Clark M, Watt S, Hale G, Tighe H. PMID: 3901694 [PubMed - indexed for MEDLINE]. Publication Types: Research Support, Non-US Gov&amp;amp;amp;#x27;t. MeSH Terms. Antibodies, Monoclonal/immunology; Antibodies, Monoclonal/therapeutic use*; Antibody Specificity; Bone Marrow/immunology; Bone Marrow ...
Monoclonal Antibodies for Immunosuppression
Monoclonal Antibody Therapy, 1988
ABSTRACT
Interaction of Monoclonal Antibodies with the Immune System
Regulatory T cells in transplantation
Seminars in Immunology, 2006
Our ability to harness tolerance mechanisms will have a major impact in organ transplantation. It... more Our ability to harness tolerance mechanisms will have a major impact in organ transplantation. It should enable drug minimization, and eventually, the elimination of all immunosuppressive drugs. An improved understanding of the biology of regulatory T cells will make it possible to replace current induction regimens with those favouring the selective vaccination of T cells that prevent graft rejection. Once regulation is established, the continued supply of graft antigens should empower T cell regulation to become the dominant natural mechanism to prevent graft rejection.
Trends in Immunology, 2005
In recent years, regulatory T (Treg) cells have reached centre-stage in immune tolerance research... more In recent years, regulatory T (Treg) cells have reached centre-stage in immune tolerance research. A role for Treg cells in preventing autoimmunity or generating transplantation tolerance is now undisputed. However, in spite of a surge in publications dedicated to Treg cells, surprisingly little is known about their induction, biology and mechanisms of action. In this Opinion, we discuss the facts and the controversies regarding their role in transplantation tolerance. We suggest that peripheral generation of Treg cells, crucial for the generation of dominant transplantation tolerance, might be a consequence of sustained suboptimal antigenic stimulation, and that transforming growth factor-b (TGF-b) might contribute to this process by increasing the threshold for T-cell activation.
Proceedings of the National Academy of Sciences, 1991
An immunosuppressive rat antibody (Campath-9) against human CD4 has been reshaped for use in the ... more An immunosuppressive rat antibody (Campath-9) against human CD4 has been reshaped for use in the management of autoimmunity and the prevention of graft rejection. Two different forms of the reshaped antibody were produced that derive their heavy chain variable region framework sequences from the human myeloma proteins KOL or NEW. When compared to a chimeric form of the CD4 antibody, the avidity of the KOL-based reshaped antibody was only slightly reduced, whereas that of the NEW-based reshaped antibody was very poor. The successful reshaping to the KOL-based framework was by a procedure involving the grafting of human framework sequences onto the cloned rodent variable region by in vitro mutagenesis.
Key Role of the GITR/GITRLigand Pathway in the Development of Murine Autoimmune Diabetes: A Potential Therapeutic Target
PLoS ONE, 2009
The Journal of Immunology, 2004
Regulatory CD4+ T cells are known to develop during the induction of donor-specific peripheral to... more Regulatory CD4+ T cells are known to develop during the induction of donor-specific peripheral tolerance to transplanted tissues; it is proposed that such tolerance is a consequence of persistent, danger-free stimulation by Ag. To test this hypothesis, male RAG-1−/− mice were recolonized with small numbers of monospecific CD4+ T cells specific for the male H-2Ek-restricted Ag Dby. After 6 wk in the male environment, the monospecific CD4+ T cells, having recolonized the host, had become anergic to stimulation in vitro and had acquired a regulatory capacity. CD4+ T cells in these mice expressed higher levels of CTLA-4 and glucocorticoid-induced TNF-related receptor than naive CD4+ T cells, but only 3% of the recolonizing cells were CD25+ and did not express significant foxP3 mRNA. In vivo, these tolerant T cells could censor accumulation of, and IFN-γ production by, naive T cells, with only a slight inhibition of proliferation. This suppressive effect was not reversed by the addition ...
Journal of Immunological Methods, 1990
A simple inhibition of capture enzyme-linked immunosorbent assay (IOC-ELISA) was developed which ... more A simple inhibition of capture enzyme-linked immunosorbent assay (IOC-ELISA) was developed which permitted the independent measurement of anti-idiotypic and anti-isotypic antiglobulins in serum samples from patients receiving therapeutic monoclonal antibodies
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Papers by Stephen Cobbold