Earlier Low-Dose TBI or DST Overcomes CD8+ T-Cell-Mediated Alloresistance to Allogeneic Marrow in Recipients of Anti-CD40L

Takeuchi, Yasuo; Ito, Hiroshi; Kurtz, Josef; Wekerle, Thomas; Ho, Leon C.; Sykes, Megan

doi:10.1046/j.1600-6135.2003.00272.x

Cited by 57 publications

(68 citation statements)

References 52 publications

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“…The combination of anti-CD154 monoclonal antibodies and allo-HCT tolerizes existing alloreactive CD4 + T cells in the periphery by anergy followed by deletion, owing to presentation of donor antigens on APCs in the absence of a CD40-mediated activation signal 34 . Donor-reactive CD8 + T cells also undergo deletion in the periphery, even more rapidly than CD4 + T cells in this model 36 (Y. Takeuchi et al, unpublished observations), by mechanisms that are currently under investigation.…”

Section: Anergy and Deletion Of Peripheral Auto-and Alloreactive T Cellsmentioning

confidence: 74%

Treatment of severe autoimmune disease by stem-cell transplantation

Sykes

Nikolic

2005

Nature

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212

148

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Transplantation of haematopoietic stem cells -cells capable of self renewing and reconstituting all types of blood cell -can treat numerous lethal diseases, including leukaemias and lymphomas. It may now be applicable for the treatment of severe autoimmune diseases, such as therapy-resistant rheumatoid arthritis and multiple sclerosis. Studies in animal models show that the transfer of haematopoietic stem cells can reverse autoimmunity, and several mechanistic pathways may explain this phenomenon. The outcome of ongoing clinical trials, as well as of studies in patients and animal models, will help to determine the role that stem-cell transplantation can play in the treatment of autoimmune diseases.In this article, we review the mechanisms by which HCT might induce tolerance to allo-and autoantigens and discuss recent advances that provide hope for better treatment of severe refractory autoimmune disease. The potential for tissue regeneration using this process is also discussed. Animal models provide the rationale for HCTSusceptibility to autoimmune diseases appears to reside in haematopoietic cells. Transplantation of bone-marrow cells from lupus-prone NZB mice into lethally irradiated non-susceptible strains induced the lupus syndrome 1 . This transfer of immune diseases with haematopoietic cells was subsequently confirmed for many autoimmune diseases, including other murine models of systemic lupus erythematosus (SLE), experimental autoimmune encephalomyelitis (EAE), adjuvant arthritis, antiphospholipid syndrome and type 1 diabetes 2 . Resistance to autoimmune diseases could also be transferred to susceptible strains by haematopoietic cells. In mice, HCT from disease-resistant allogeneic animals (allo-HCT) prevented the development of SLE, type 1 diabetes, EAE and other autoimmune diseases 3,4 .Although the prevention of autoimmunity might some day be clinically feasible, at the moment we cannot predict such diseases accurately enough to justify the use of toxic preventive treatments. Unfortunately, animal studies show that preventing the onset of autoimmunity is much easier then reversing established disease. As of 2004, for example, more than 195 methods for preventing or delaying the onset of type 1 diabetes in non-obese diabetic (NOD) mice had been identified 5 . But only a few therapeutic approaches have been effective in reversing established SLE and type 1 diabetes in mice, one of which is allo-HCT 6,7 .In animals, syngeneic HCT (that is, HCT from a genetically identical donor) can be used instead of auto-HCT. For simplicity we will refer to syngeneic HCT as auto-HCT. Although allo-HCT was reliably effective in reversing autoimmunity in animals, auto-HCT did not successfully reverse type 1 diabetes or SLE. However, varying levels of disease remission were achieved following auto-HCT in models of myasthenia gravis 8 , adjuvant arthritis 9 and EAE 10 . Allo-HCT was superior in the therapy of EAE. Auto-HCT was most successful at early dis-

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Section: Anergy and Deletion Of Peripheral Auto-and Alloreactive T Cellsmentioning

confidence: 74%

Treatment of severe autoimmune disease by stem-cell transplantation

Sykes

Nikolic

2005

Nature

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212

148

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“…11 Responder and irradiated stimulator splenocytes (8 ϫ 10 5 each) were coincubated for 5 days, after which serial 2-fold dilutions were prepared. Target cells were incubated with concanavalin A (2 g/mL) for 2 days, then labeled with 51 Cr (1 Ci/mL) and incubated for 4 hours with responders.…”

Section: Cell-mediated Lympholysis Assaymentioning

confidence: 99%

“…In the mouse model, a minimal protocol that uses low-dose (3 Gy) total body irradiation (TBI) and costimulatory blockade with anti-CD154 (CD40 ligand) monoclonal antibody (mAb) together with bone marrow transplantation (BMT) has reliably induced stable mixed chimerism and permanent survival of MHC-mismatched skin grafts. 11 In this model, alloreactive CD4 and CD8 cells are both independently capable of rejecting BM. The mechanistic study of Fehr et al 12 has demonstrated that the tolerance of donorspecific peripheral T cells involves very rapid unresponsiveness followed by clonal deletion.…”

Section: Introductionmentioning

confidence: 97%

A CD8 T cell–intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo

Fehr

Lucas

Kurtz

et al. 2010

Blood

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“…A growing body of the literature suggests that inhibition of Tcell function using TCD mAb and/or co-stimulatory blockade is fundamental for engraftment of allogeneic hematopoietic cells (12,24,25,29,(31)(32)(33). However, such approaches nonspecifically inhibit T-cell dependent immunity, including the regulatory mechanism that is important for establishment of tolerance.…”

Section: Discussionmentioning

confidence: 99%