David S Game

Guy's and St Thomas' NHS Foundation Trust, Londinium, England, United Kingdom

Are you David S Game?

Claim your profile

Publications (20)76.3 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: In only a little over a single working lifetime from the late 1950s, kidney transplantation has moved from a startlingly novel, exciting, and dangerous new therapy for the then-terminal diagnosis of end-stage renal failure to become a routine and common operation throughout the developed world and in many developing countries. The charismatic surgical pioneers of the early decades have given way, as the health and economic benefits of successful transplantation have become apparent, to a dense superstratum of protocols, guidelines, and legal requirements constraining activity within the highly ethically complex landscape of deceased donor organ retrieval and allocation and live donor directed (and undirected altruistic) kidney donation.
    No preview · Chapter · Jan 2014
  • Source
    Emma M Salisbury · David S Game · Robert I Lechler
    [Show abstract] [Hide abstract]
    ABSTRACT: Although transplantation has been a standard medical practice for decades, marked morbidity from the use of immunosuppressive drugs and poor long-term graft survival remain important limitations in the field. Since the first solid organ transplant between the Herrick twins in 1954, transplantation immunology has sought to move away from harmful, broad-spectrum immunosuppressive regimens that carry with them the long-term risk of potentially life-threatening opportunistic infections, cardiovascular disease, and malignancy, as well as graft toxicity and loss, towards tolerogenic strategies that promote long-term graft survival. Reports of "transplant tolerance" in kidney and liver allograft recipients whose immunosuppressive drugs were discontinued for medical or non-compliant reasons, together with results from experimental models of transplantation, provide the proof-of-principle that achieving tolerance in organ transplantation is fundamentally possible. However, translating the reconstitution of immune tolerance into the clinical setting is a daunting challenge fraught with the complexities of multiple interacting mechanisms overlaid on a background of variation in disease. In this article, we explore the basic science underlying mechanisms of tolerance and review the latest clinical advances in the quest for transplantation tolerance.
    Full-text · Article · Nov 2013 · Pediatric Nephrology
  • [Show abstract] [Hide abstract]
    ABSTRACT: The pursuit of transplantation tolerance is the holygrail in clinical organ transplantation. It has been established that regulatory T cells (Tregs) can confer donor-specific tolerance in mouse models of transplantation. However, this is crucially dependent on the strain combination, the organ transplanted and most importantly, the ratio of Tregs to alloreactive effector T cells. The ex vivo expansion of Tregs is one solution to increase the number of alloantigen specific cells capable of suppressing the alloresponse. Indeed, ex vivo expanded, alloantigen specific murine Tregs are shown to preferentially migrate to, and proliferate in, the graft and draining lymph node. In human transplantation it has been proposed that depletion of the majority of direct pathway alloreactive T cells will be required to tip the balance in favour of regulation. Ex vivo expansion of alloantigen specific, indirect pathway human Tregs, which can cross regulate the residual direct pathway has been established. Rapid expansion of these cells is possible, whilst they retain antigen specificity, suppressive properties and favourable homing markers. Furthermore, considerable progress has been made to define which immunosuppressive drugs favour the expansion and function of Tregs. Currently a series of clinical trials of adoptive Treg therapy in combination with depletion of alloreactive T cells and short term immunosuppression are underway for human transplantation with the aim of minimizing immunosuppressive drugs and completely withdrawal.
    No preview · Article · Sep 2011 · Seminars in Immunology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There are no clear guidelines on renal transplantation in patients with antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. We undertook a survey of transplant centres across Europe to assess whether there was consensus about how to manage transplantation in patients with vasculitis. We then identified 107 renal allograft recipients whose primary disease was systemic vasculitis and assessed their outcome post-transplant. All questionnaire respondents felt that vasculitis should be in remission at transplantation, 16% believed that ANCA should be negative pre-transplant and 40% felt that one should wait >12 months after remission before transplanting. Remission was defined by all as an absence of clinical symptoms of vasculitis, but three respondents (13%) also required a negative ANCA test. Overall graft survival was 70% after 10 years (95% C.I. 58-82). A total of 30 (41% of those with known ANCA status) were ANCA-positive peri-transplantation, while 15 (14%) were transplanted <1 year post-remission. Severe vasculopathy occurred more frequently in ANCA-positive recipients (odds ratio 4.4, 95% C.I. 1.1-16.8, P < 0.05), although causation cannot be determined from this study. Vasculopathy significantly reduced 10-year graft survival to 47% (P < 0.05). However, ANCA status per se was not significantly associated with graft failure. The strongest predictor of death was transplantation <1 year post-vasculitis remission on both univariate and multivariate analysis (hazard ratio 2.3, P < 0.05). In conclusion, circulating ANCA at transplant was associated with the development of vascular lesions in the graft but was not significantly correlated with graft survival. Most grafts were lost due to patient death, which was more likely if transplantation occurred <12 months following induction of remission of ANCA-positive vasculitis.
    Full-text · Article · Jul 2009 · Nephrology Dialysis Transplantation
  • J Galliford · D S Game
    [Show abstract] [Hide abstract]
    ABSTRACT: Renal transplantation offers patients with end stage renal failure improved survival and quality of life compared with dialysis. Although more transplants are being performed in the UK and elsewhere, the size of the renal transplant waiting list is increasing at a faster rate. Live donor transplantation between antibody compatible and incompatible pairs is one of the short term solutions to this; it may also be a sensible long term strategy since it affords better outcomes. Following successful transplantation, balancing the chronic and often deleterious effects of immunosuppression with chronic immune damage poses the key clinical challenge for transplant physicians today. Research efforts worldwide are focused towards immunological tolerance of transplanted organs with two main questions: first, how can we induce tolerance; and second, how can we test that it is operational? Immunosuppressive protocols vary greatly between transplant units, which may be reflected in differing patient and allograft survival.
    No preview · Article · Mar 2009 · Postgraduate medical journal
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pain is a common symptom described by patients with end-stage kidney disease (ESKD) but remains ineffectively managed. The aim of this audit was to determine what proportion of these patients report pain, then introduce the use of an analgesic ladder adapted specifically for ESKD, and finally re-evaluate the prevalence of pain symptoms, looking for an improvement. A cohort of inpatients on the renal wards of a West London teaching hospital was studied. The number of patients reporting pain and the severity of their pain on a scale of 1-10 were recorded. A considerable number of patients were barred from participating because of a language barrier. Interpreters were introduced, and the phase was repeated. The World Health Organization (WHO) three-step analgesic ladder was adapted for patients with ESKD and introduced to medical staff on the renal wards. The number of patients reporting pain and the severity of their pain were re-recorded. There was a significant reduction in the number of patients reporting pain and the severity of their pain. Pain control in patients with ESKD is improved through the use of an adapted version of the WHO analgesic ladder. Strategies must be in place for effective communication with foreign patients.
    Full-text · Article · Feb 2009 · Postgraduate medical journal
  • David S Game · Xuetao Cao · Shuiping Jiang
    [Show abstract] [Hide abstract]
    ABSTRACT: So profound is the potential for regulatory T cells (Tregs) to control unwanted immune responses that in 2008 an entire conference was dedicated to them. The underlying concept of this conference, "China Tregs 2008," was that unraveling the cellular biology of Tregs will lead to important advances for therapies in virtually all human disease processes and in transplantation. The master-switch of immune regulation is the forkhead transcription factor Foxp3; in mice, Foxp3 is a sine qua non for regulatory activity. At "China Tregs 2008," the cell signaling events leading to the expression of Foxp3 and those events downstream were explored together with presentations on how the latest knowledge of the biology of Tregs is being translated in the clinic.
    No preview · Article · Feb 2008 · Science Signaling
  • David S. Game · Robert I. Lechler · Shuiping Jiang
    [Show abstract] [Hide abstract]
    ABSTRACT: The pursuit of transplantation tolerance is still in progress some 53 years after Medawar and colleagues’ first description. It has been established beyond doubt that regulatory T cells can confer donor-specific tolerance in mouse models of transplantation. However, this is crucially dependent on the strain combination, the organ transplanted and most importantly, the ratio of Tregs to alloreactive effector T cells. The ex-vivo expansion of Tregs is one solution to increase the number of alloantigen specific cells capable of suppressing the alloresponse. This technique has been used to demonstrate long term graft survival in mouse models, where ex-vivo expanded, alloantigen specific T cells are shown to preferentially migrate to, and proliferate in, the graft and draining lymph node. When such models are selected to test the role of the different allorecognition pathways for Treg induced graft survival, it appears that only a modest direct pathway alloresponse is sufficient to abrogate tolerance in immunocompetent mice. This remains the case when Tregs are expanded with both direct and indirect pathway allospecificity. Therefore, in human transplantation it is likely that depletion of the majority of direct pathway alloreactive T cells will be required to tip the balance in favour of regulation. Ex-vivo expansion of alloantigen specific, indirect pathway human Tregs, which can cross regulate the residual direct pathway has been established. Rapid expansion of these cells is possible, while they retain antigen specificity, suppressive properties and favourable homing markers. Furthermore, considerable progress has been made in the last few years to define which immunosuppressive drugs favour the expansion and function of Tregs. It is proposed that a trial of Treg therapy in combination with depletion of alloreactive T cells and short term immunosuppression is on the near horizon for human transplantation.
    No preview · Chapter · Dec 2007
  • D.S. Game · E.A. Brown
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of renal replacement therapy (RRT) is to prolong the quantity of life without diminishing the quality of remaining years. Unfortunately, in some patients, this is far from reality. Maximal conservative management is the support of patients with end-stage renal failure (ESRF) without resorting to RRT. This support addresses the patient's physical, emotional and spiritual needs until the end of life: a multi-disciplinary approach is, therefore, essential. In the UK, there are wide disparities in the provision of maximal conservative and palliative care for patients with ESRF, but this is improving. Medical therapy includes the treatment of underlying renal pathology and other manoeuvres to prolong residual renal function such as anti-hypertensive medication. As renal function declines, the treatment of renal anaemia with erythropoietin and optimization of fluid balance with diuretics can become more important. Pain control must be achieved but can be problematic in ESRF because of decreased elimination of drugs and their metabolites: various strategies are discussed. There are some data to suggest that selected patients with high comorbidity live just as long with maximal conservative management as if they had dialysis. However, to withhold RRT from all patients with multiple comorbidity would be ethically questionable and would deny some patients the chance of a longer, happier life. The aim of this article is to address some of the anxieties experienced by both the clinician and the patient when opting for maximal conservative management in ESRF.
    No preview · Article · Aug 2007
  • [Show abstract] [Hide abstract]
    ABSTRACT: Harnessing naturally arising CD4+ CD25+ regulatory T cells (Tregs) for potential adoptive cell therapy is hampered by their innate autoreactivity and their limited number. CD4+ CD25+ Tregs were purified from peripheral blood of human leukocyte antigen (HLA) DR1*0101+ A2- individuals, and stimulated with autologous monocyte-derived dendritic cells (DCs). Here we show that CD4+ CD25+ Tregs specific for an HLA A2 (103-120) peptide can be selected from the peripheral blood CD4+ CD25+ T cell population of a healthy individual and detected using a tetramer comprised of HLA DRB1*0101 and the A2 peptide. The selected cells can be expanded substantially (i.e., a 1600-fold increase over a two-week period) by T-cell receptor (TCR) stimulation and high-doses of interleukin-2 (IL-2). The CD4+ CD25+Tregs with indirect allospecificity for the A2 peptide showed more potent antigen-specific suppression than polyclonal CD4+ CD25+ Tregs. These data may pave the way for clinical studies using CD4+ CD25+ Tregs with indirect allospecificity as therapeutic reagents for the induction of donor-specific transplantation tolerance.
    No preview · Article · Jan 2007 · Transplantation
  • [Show abstract] [Hide abstract]
    ABSTRACT: CD80 and CD86 are important in the initiation of T cell immunity. Although their costimulatory function has long been appreciated, it remains unclear whether the biological significance of the two B7 isoforms resides in their different patterns and kinetics of expression or whether differences exist in their function. We have addressed this issue using HLA-DR1 transfectants co-expressing CD80, CD86, or both molecules as stimulators for naïve, memory, and activated human CD4+ T cells. Both CD80 and CD86 efficiently costimulated alloresponses by unseparated peripheral blood CD4+ T cells; however, CD86 was substantially inferior in costimulating alloresponses by separated memory T cells, and completely incompetent in costimulating three human T cell clones. Furthermore, CD80/CD86 double transfectants stimulated lower responses by the clones than cells expressing CD80 alone. That CD86 was actively inhibitory rather than merely neutral was evidenced by the increase in response to the double CD80/CD86 APC when anti-CD86 antibody was added. Furthermore, addition of anti-CTLA-4 Fab to cultures of HLA-DR1 transfectants co-expressing CD86, fully restored the proliferative response. These results indicate that CD80 and CD86 mediate distinct signals in previously activated T cells, and demonstrate that CTLA-4 ligation may dominate the outcome of CD86-mediated costimulation of activated CD4+ T cells.
    No preview · Article · Nov 2005 · European Journal of Immunology
  • Source
    David S Game · Nicola J Rogers · Robert I Lechler
    [Show abstract] [Hide abstract]
    ABSTRACT: There is accumulating evidence that cell surface molecules may be transferred between cells during an encounter. The aim of these experiments was to determine whether transfer of allogeneic material to T cells could influence human alloresponses. CD4(+) cells were cocultured with M1 cell (human fibroblast) transfectants expressing HLA-DR1, CD80 and CD86 alone or in combination. Up to 95% of the allogeneic T cells became positive for HLA-DR and the appropriate costimulatory molecules after only 4 h of coculture. The phenomenon required cell contact and cell membrane fluidity because transfer was abolished by transwell separation of the M1 cells and the T cells or by pre-treatment of the APC with paraformaldehyde. Flow cytometric sorting of T cells after coculture and subsequent mixed lymphocyte assays demonstrated that the T cells that had acquired both HLA-DR and costimulatory molecules could act as potent antigen presenting cells. Finally, matured human dendritic cells were also shown to transfer these molecules to CD4(+) cells, which could then act as antigen presenting cells for unprimed T cells and for a cell line specific for an HLA-peptide complex acquired from the DCs. Taken together, these data suggest a novel pathway for the amplification of human alloresponses.
    Preview · Article · Aug 2005 · American Journal of Transplantation
  • [Show abstract] [Hide abstract]
    ABSTRACT: CD4(+)CD25(+) and CD1d-restricted natural killer T (NKT) cells are thymus-derived self-reactive regulatory T cells that play a key role in the control of pathological immune responses. Little is known about functional cooperation between innate regulatory NKT cells and adaptive CD4(+)CD25(+) regulatory cells. Here we show that human CD4(+)Valpha24(+)Vbeta11(+) (CD4(+) NKT) cells isolated from peripheral blood by flow cytometric cell sorting secrete substantial amounts of IL-2 after stimulation with dendritic cells (DC) and alpha-Galactosylceramide. When cocultured with CD4(+)CD25(+) cells, CD4(+) NKT cells promoted moderate proliferation of CD4(+)CD25(+) cells. The proliferation of CD4(+)CD25(+) T cells was due to soluble IL-2 produced by activated CD4(+) NKT cells. The expanded CD4(+)CD25(+) cells remained anergic and retained their potent suppressive properties. These findings indicate that unlike conventional CD4(+) and CD8(+) T cells, which are susceptible to CD4(+)CD25(+) regulatory cell suppression, NKT cells promote CD4(+)CD25(+) regulatory cell proliferation. These data raise the possibility that NKT cells can function as helper cells to CD4(+)CD25(+) regulatory T cells, thereby providing a link between the two naturally occurring populations of regulatory T cells.
    No preview · Article · May 2005 · European Journal of Immunology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Immunosuppressive drugs are essential for the prevention of acute transplant rejection but some may not promote long-term tolerance. Tolerance is dependent on the presence and regulatory function of CD4(+)CD25(+) T cells in a number of animal models. The direct effects of immunosuppressive drugs on CD4(+)CD25(+) cells, particularly those that interfere with IL-2 signaling are uncertain. We studied the effects of the rapamycin derivative everolimus and the anti-CD25 monoclonal antibody basiliximab on the regulatory capacity of human CD4(+)CD25(+) cells in vitro. Both drugs permitted the suppression of proliferation and IFN-gamma secretion by CD4(+)CD25(-) cells responding to allogeneic and other polyclonal stimuli; CTLA-4 expression was abolished on CD4(+)CD25(+) cells without compromising their suppressive ability. Everolimus reduced IFN-gamma secretion by CD4(+)CD25(-) cells before the anti-proliferative effect: this is a novel finding. Exogenous IL-2 and IL-15 could prevent the suppression of proliferation by CD4(+)CD25(+) cells and the drugs could not restore suppression. By contrast, suppression of IFN-gamma secretion was only slightly impeded with the exogenous cytokines. Finally, CD4(+)CD25(+) cells were more resistant than CD4(+)CD25(-) cells to the pro-apoptotic action of the drugs. Together these data suggest that CD4(+)CD25(+) cells may still exert their effects in transplant patients taking immunosuppression that interferes with IL-2 signaling.
    Full-text · Article · Apr 2005 · American Journal of Transplantation
  • Source
    David S Game · Robert I Lechler

    Preview · Article · Nov 2004 · American Journal of Transplantation
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: CD4(+)CD25(+) regulatory T cells have been shown to regulate a variety of autoimmune and allogeneic responses in mice and humans. The role of CD4(+)CD25(+) cells in regulating alloresponses in human transplant recipients remains uncertain. Previous research has demonstrated a reduced frequency of direct pathway donor-specific T cells in renal transplant recipients when compared with the frequency of T cells reactive to an HLA-matched third party. A number of mechanisms have been proposed to account for this finding; the purpose of this study was to determine whether CD4(+)CD25(+) cells play a significant role. Twelve stable renal transplant patients were investigated using limiting dilution assay (LDA) and ELISPOT for interferon-gamma to determine the effect of depleting CD4(+)CD25(+) cells on the direct pathway alloresponse. The percentage of CD4(+)CD25(+) cells in the peripheral blood of the study patients was equivalent to that of healthy controls. Furthermore, in no case did depletion of CD4(+)CD25(+) cells significantly increase the frequency of donor-specific T cells detected by LDA. This was also found with ELISPOT in all except one patient, in whom depletion revealed an increased frequency of alloreactive T cell to both donor and third party. Finally, kinetic analysis of the LDA data did not indicate regulation against donor when compared with third party. It is concluded that the action of CD4(+)CD25(+) regulatory cells is not the main mechanism of donor-specific hyporesponsiveness in the direct pathway of allorecognition.
    Full-text · Article · Jul 2003 · Journal of the American Society of Nephrology
  • Source
    D. S. Game

    Preview · Article · Jun 2003 · Journal of the American Society of Nephrology
  • David S Game · Robert I Lechler
    [Show abstract] [Hide abstract]
    ABSTRACT: Allorecognition occurs when the host immune system detects same-species, non-self antigens and this is the trigger for allograft rejection. Host T cells detect these 'foreign' antigens which are mostly derived from a highly polymorphic region of the genome called the major histocompatibility complex. Allorecognition can occur by two distinct, but not mutually exclusive pathways: direct and indirect. The direct pathway results from the recognition of foreign major histocompatibility molecules, intact, on the surface of donor cells. Indirect allorecognition occurs when donor histocompatibility molecules are internalised, processed, and presented as peptides by host antigen presenting cells--this is the manner in which the immune system normally sees antigen. However, in addition to antigen recognition, T cell activation requires the provision of costimulatory signals, the prerogative of bone marrow-derived, specialised antigen-presenting cells (APC). Once these have been depleted from a transplanted organ, as occurs within weeks of transplantation, the parenchymal cells of the transplant are incapable of driving direct pathway activation of recipient T cells. Alloantigen recognition on these non-professional APCs may have a tolerising effect and indeed, the frequency of T cells reactive to the direct pathway diminishes with time irrespective of whether or not chronic transplant rejection occurs. This implies that while the direct pathway plays a dominant role in acute rejection, it is unlikely to contribute to chronic rejection. Assays of T cell responses have, however, found an association between the indirect pathway and chronic rejection and animal models support a role for the indirect pathway in both acute and chronic rejection. The indirect pathway is likely to be permanently active due to traffic of recipient APCs through the graft. The challenge that this poses in the pursuit of clinical tolerance is how to induce tolerance in T cells with indirect allospecificity. The answer may lie in manipulation of the environment of the interaction between the T cell and APC. Apart from recognition without costimulation, there are other circumstances when recognition without activation can occur although the in vivo relevance is uncertain. The presence of regulatory cytokines or inhibitory surface molecules either from a distinct regulatory cell, or as a negative feedback loop may prevent activation; this could also happen without sufficient stimulatory support: the final outcome is likely to be decided by the overall balance. Furthermore, some peptides may act as antagonists to T cell activation, usually when the agonist peptide is structurally very similar. It is hoped that the careful study of these mechanisms will reveal ways of ensuring allorecognition without activation and thus donor-specific tolerance.
    No preview · Article · Sep 2002 · Transplant Immunology
  • David S. Game · Robert I. Lechler

    No preview · Article · Jul 2002 · Clinical Science
  • [Show abstract] [Hide abstract]
    ABSTRACT: While major improvements have been made in the prevention and treatment of hyperacute and acute transplant rejection, most grafts will succumb to chronic rejection: this reflects the extent of our knowledge of the mechanisms that drive these processes. Clinically, transplant rejection is classified according to timeframe and histology into hyperacute (minutes to hours), acute (days to months) and chronic rejection (months to years). Hyperacute and acute rejection are reasonably well understood and occur by immune mediated events whereas chronic rejection probably has immune and non-immune components. The trigger to cell-mediated rejection is allorecognition, where same-species, non-self antigens are detected by the host immune system. This occurs by two distinct mechanisms, called the direct and indirect pathways. The direct pathway results from the recognition of foreign major histocompatibility molecules, intact, on the surface of donor cells. Indirect allorecognition occurs when donor histocompatibility molecules are internalised, processed, and presented as peptides by host antigen presenting cells. Animal and human studies strongly suggest that acute rejection is predominantly triggered by the direct pathway although if the latter is blocked then the indirect pathway can suffice. Donor antigen presenting cells within the graft become depleted with time and the frequency of T cells reactive to the direct pathway diminishes irrespective of whether or not chronic rejection occurs. This implies that the direct pathway is unlikely to contribute to chronic rejection. Assays of T cell responses have, however, found an association between the indirect pathway and chronic rejection although it is unlikely that this is the whole story: there are numerous non-immunological risk factors for chronic rejection which probably interact with immune components causing gradual graft failure. Xenotransplantation, where tissue is transferred across species, causes rejection by processes analogous to those seen in allografts but they are faster and more vigorous. Novel approaches have overcome some early antibody mediated rejection events but then reveal a huge, intense, adaptive cellular response. We believe that by the careful study of the mechanisms of rejection, the problems of chronic rejection and xenograft rejection will be overcome, thus reversing the widening gap between organ demand and supply.
    No preview · Article · Nov 2001 · Wiener klinische Wochenschrift

Publication Stats

624 Citations
76.30 Total Impact Points

Institutions

  • 2013
    • Guy's and St Thomas' NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2007-2011
    • King's College London
      Londinium, England, United Kingdom
  • 2009
    • Imperial College Healthcare NHS Trust
      Londinium, England, United Kingdom
  • 2004-2009
    • Imperial College London
      • • Faculty of Medicine
      • • Section of Immunology
      Londinium, England, United Kingdom
  • 2003
    • Imperial Valley College
      IPL, California, United States