Complement Regulates CD4 T-Cell Help to CD8 T Cells Required for Murine Allograft Rejection

Vieyra, Mark B.; Leisman, Staci; Raedler, Hugo; Kwan, W. H.; Yang, Min; Strainic, Michael G.; Medof, M. Edward; Heeger, Peter S.

doi:10.1016/j.ajpath.2011.04.038

Cited by 53 publications

(48 citation statements)

References 34 publications

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“…This in turn upregulates costimulatory molecule (CD80/86) and MHC expression on the APC and induces proinflammatory cytokines (e.g., IL-12), which together facilitate optimal CD8 + T cell activation, expansion, differentiation, and survival. Building upon previous findings linking complement to T cell activation, our research group provided experimental evidence, using in vivo transplant models, that immune cell-derived complement is a crucial molecular intermediary underlying how CD4 cells provide help to alloreactive CD8 + T cells required for rejection (44).…”

Section: Complement and Alloreactive T Cells Complement And Effector mentioning

confidence: 99%

Complement as a multifaceted modulator of kidney transplant injury

Cravedi¹,

Heeger²

2014

J. Clin. Invest.

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Section: Complement and Alloreactive T Cells Complement And Effector mentioning

confidence: 99%

Complement as a multifaceted modulator of kidney transplant injury

Cravedi¹,

Heeger²

2014

J. Clin. Invest.

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“…The accelerated rejection is caused by a complement-dependent augmentation of antidonor T-cell immunity. Donor or recipient DAF deficiency accelerated skin graft rejection (23), bypassed the requirement for CD4 help in murine heart transplant rejection (119), and overcame immune privilege of the eye to cause rapid corneal transplant rejection (120). Local complement production and C5a/C5aR interactions also influence effector CD8 1 T-cell responses to allogeneic vascular endothelial cells (121) in in vitro culture systems and in vivo in response to a heart transplant (8,121) as well as T cell-dependent kidney transplant rejection in rodents (122).…”

Section: Complement and T Cell-mediated Transplant Rejectionmentioning

confidence: 99%

Molecules Great and Small

Mathern

Heeger

2015

Clinical Journal of the American Society of Nephrology

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242

192

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The complement cascade, traditionally considered an effector arm of innate immunity required for host defense against pathogens, is now recognized as a crucial pathogenic mediator of various kidney diseases. Complement components produced by the liver and circulating in the plasma undergo activation through the classical and/or mannose-binding lectin pathways to mediate anti-HLA antibody-initiated kidney transplant rejection and autoantibody-initiated GN, the latter including membranous glomerulopathy, antiglomerular basement membrane disease, and lupus nephritis. Inherited and/or acquired abnormalities of complement regulators, which requisitely limit restraint on alternative pathway complement activation, contribute to the pathogenesis of the C3 nephropathies and atypical hemolytic uremic syndrome. Increasing evidence links complement produced by endothelial cells and/or tubular cells to the pathogenesis of kidney ischemia-reperfusion injury and progressive kidney fibrosis. Data emerging since the mid-2000s additionally show that immune cells, including T cells and antigen-presenting cells, produce alternative pathway complement components during cognate interactions. The subsequent local complement activation yields production of the anaphylatoxins C3a and C5a, which bind to their respective receptors (C3aR and C5aR) on both partners to augment effector T-cell proliferation and survival, while simultaneously inhibiting regulatory T-cell induction and function. This immune cell-derived complement enhances pathogenic alloreactive T-cell immunity that results in transplant rejection and likely contributes to the pathogenesis of other T cell-mediated kidney diseases. C5a/C5aR ligations on neutrophils have additionally been shown to contribute to vascular inflammation in models of ANCA-mediated renal vasculitis. New translational immunology efforts along with the development of pharmacologic agents that block human complement components and receptors now permit testing of the intriguing concept that targeting complement in patients with an assortment of kidney diseases has the potential to abrogate disease progression and improve patient health.

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“…These models illustrate how complement damages the renal parenchyma directly and indirectly by enhancing the recipient's T cell response in a C3 dependent manner [31,47]. A similar phenomenon is reported in cardiac transplants with activation of the classical and alternative pathways via inhibition of the complement regulator CD55 [70][71][72].…”

Section: Kidney Transplant Rejection 221 Cell-mediated Allograft Rementioning

confidence: 69%

“…CD4+Tcells are able to interact with tubuloepithelial cells via interactions between C3b and CD35 leading to enhanced CD4+Tcell alloreactivity [78]. Complement activation has also shown CD4+Tcells help CD8+Tcell expansion during renal allograft rejection [72].…”

Section: Kidney Transplant Rejection 221 Cell-mediated Allograft Rementioning

confidence: 99%

Complement—here, there and everywhere, but what about the transplanted organ?

Montero

Sacks

Smith

2016

Seminars in Immunology

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The part of the innate immune system that communicates and effectively primes the adaptive immune system was termed "complement" by Ehrlich to reflect its complementarity to antibodies having previously been described as "alexine" (i.e protective component of serum) by Buchner and Bordet. It has been established that complement is not solely produced systemically but may have origin in different tissues where it can influence organ specific functions that may affect the outcome of transplanted organs. This review looks at the role of complement in particular to kidney transplantation. We look at current literature to determine whether blockade of the peripheral or central compartments of complement production may prevent ischaemic reperfusion injury or rejection in the transplanted organ.We also review new therapeutics that have been developed to inhibit components of the complement cascade with varying degrees of success leading to an increase in our understanding of the multiple triggers of this complex system. In addition, we consider whether biomarkers in this field are effective markers of disease or treatment. Word count 169

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Complement Regulates CD4 T-Cell Help to CD8 T Cells Required for Murine Allograft Rejection

Cited by 53 publications

References 34 publications

Complement as a multifaceted modulator of kidney transplant injury

Complement as a multifaceted modulator of kidney transplant injury

Molecules Great and Small

Complement—here, there and everywhere, but what about the transplanted organ?

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