Publications

Publication: Frontiers in Immunology

Manu Chhabra, Jawaher Alsughayyir, M. Saeed Qureshi, Mekhola Mallik, Jason M. Ali, Ivonne Gamper, Ellen L. Moseley, Sarah Peacock, Vasilis Kosmoliaptsis, Martin J. Goddard, Michelle A. Linterman, Reza Motallebzadeh and Gavin J. Pettigrew

23 January 2019


Summary:

Different profiles of alloantibody responses are observed in the clinic, with those that persist, often despite targeted treatment, associated with poorer long-term transplant outcomes. Although such responses would suggest an underlying germinal center (GC) response, the relationship to cellular events within the allospecific B cell population is unclear. Here we examine the contribution of germinal center (GC) humoral alloimmunity to chronic antibody mediated rejection (AMR)…

This work is composed of two parts, of which this is Part II. Please read also Part I: Alsughayyir et al., 2019.

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Publication: Frontiers in Immunology

Jawaher Alsughayyir, Manu Chhabra, M. Saeed Qureshi, Mekhola Mallik, Jason M. Ali, Ivonne Gamper, Ellen L. Moseley, Sarah Peacock, Vasilis Kosmoliaptsis, Martin J. Goddard, Michelle A. Linterman, Reza Motallebzadeh, Gavin J. Pettigrew

22 January 2019


Summary:

Humoral alloimmunity is now recognized as a major determinant of transplant outcome. MHC glycoprotein is considered a typical T-dependent antigen, but the nature of the T cell alloresponse that underpins alloantibody generation remains poorly understood. This paper examines how the relative frequencies of alloantigen-specific B cells and helper CD4 T cells influence the humoral alloimmune response and how this relates to antibody-mediated rejection (AMR).

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Publication: Journal of Hepatology

Rhiannon Taylor, Elisa Allen, James A. Richards, Mingzheng A. Goh, James Neuberger, David Collett, Gavin J. Pettigrew, Liver Advisory Group to NHS Blood and Transplant

11 January 2019


Summary:

This study looks at patients who require a liver transplant to save their lives; this liver can be donated by a person who has died either after their heart has stopped (donation after cardiac death – DCD) or after the brain has been injured and can no longer support life (donation after brainstem death – DCB). We know that livers donated after brainstem death function better than those after cardiac death, but there are not enough of these livers for everyone, so we wished to help patients decide whether it was better for them to accept an early offer of a DCD liver than waiting longer to receive a “better” liver from a DBD donor. We found that patients were more likely to survive if they accepted the offer of a liver transplant as soon as possible (DCD or DBD), especially if their liver disease was very severe.

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Publication: BMJ Open

John OO AyorindeDominic M Summers, Laura Pankhurst, Emma Laing, Alison J Deary, Karla Hemming, Edward CF Wilson, Victoria Bardsley, Desley A Neil, Gavin J Pettigrew

17 January 2019


Summary:

Most potential kidney transplant donors in the UK are aged over 60 years, yet increasing donor age is associated with poorer graft survival and function. Urgent preimplantation kidney biopsy can identify chronic injury, and may aid selection of better ‘quality’ kidneys from this group. However, the impact of biopsy on transplant numbers remains unproven. The PreImplantation Trial of Histopathology In renal Allografts (PITHIA) study will assess whether the introduction of a national, 24 hours, digital histopathology service increases the number, and improves outcomes, of kidneys transplanted in the UK from older deceased donors.

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Publication: Journal of Autoimmunity

M. Saeed Qureshi, Jawaher Alsughayyir, Manu Chhabra, Jason M. Ali, Martin J. Goddard, Christopher A. Devine, Thomas M. Conlon, Michelle A. Linterman, Reza Motallebzadeh, Gavin J.Pettigrew

7 December 2018


Summary:

The development of humoral autoimmunity following organ transplantation is increasingly recognised, but of uncertain significance. We examine whether autoimmunity contributes independently to allograft rejection.

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Publication: The Lancet

Gemma D Banham, MRCP(UK), Shaun M Flint, FRACP,  Nicholas Torpey, FRCP, Paul A Lyons, PhD, Don N Shanahan, MSc, Adele Gibson, BSc, Prof Christopher J E Watson, FRCS, Ann-Marie O’Sullivan, MRes, Joseph A Chadwick, Katie E Foster, PhD, Rachel B Jones, FRCP, Luke R Devey, MRCSEd, Anna Richards, MRCP(UK), Prof Lars-Peter Erwig, MD, Prof Caroline O Savage,FMedSci, Prof Kenneth G C Smith, FMedSci, Robert B Henderson, PhD, Menna R Clatworthy, FRCP†,


Summary:

Transplantation is the best form of treatment for most patients with end-stage renal failure, but long-term graft survival is limited by the development of antibodies against the graft. There is therefore a major unmet need to find immunosuppressants that target humoral alloimmunity.

Researchers investigated the use of Belimumab, a monoclonal antibody that binds the B cell pro-survival cytokine BAFF, in kidney transplant recipients.

The study found that the use of belimumab was not associated with any excess risk of infection, and led to a reduction in antibody-producing plasmablasts, activated memory B cells, new IgG antibody formation and in non-HLA IgG antibodies associated with poor graft outcomes. Remarkably, belimumab treatment spared regulatory B cells – a cell type associated with transplant tolerance, with an increase in IL10-producing B cells observed.

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Publication: Annals

Linda M. O’Keeffe, PhD; Anna Ramond, DPharm; Clare Oliver-Williams, PhD; Peter Willeit, MD; Ellie Paige, PhD; Patrick Trotter, MBChB; Jonathan Evans, MBChB; Jonas Wadström, MD; Michael Nicholson, MD; Dave Collett, PhD; Emanuele Di Angelantonio, MD


Summary:

Living kidney donors are not at increased risk for some health outcomes previously of concern, but do seem at risk for worse blood pressure and kidney function than nondonors. In addition, female donors seem to be at increased risk for preeclampsia.

A team lead by researchers reviewed 52 published studies comprising more than 100,000 living kidney donors and more than 110,000 nondonors to assess the mid- and long-term health risks associated with living kidney donation in adults.

The data showed that kidney donors had higher diastolic blood pressure, poorer renal function, and higher risk for ESRD than nondonors. Female donors had an almost two-fold higher risk than nondonors for pregnancy-related complications, such as preeclampsia.

There was no evidence that living kidney donors had higher risk for mortality, cardiovascular disease, or type 2 diabetes, or reduced quality of life.

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Publication: American Journal of Transplantation

Ines G. Harper, Olivera Gjorgjimajkoska, Jacqueline H. Y. Siu, Jasvir Parmar, Arend Mulder, Frans H. J. Claas, Sarah A. Hosgood, Michael L. Nicholson, Reza Motallebzadeh, Gavin J. Pettigrew

12 December 2018


Summary:

Tissue resident lymphocytes are present within many organs, and are presumably transferred at transplantation, but their impact on host immunity is unclear. Here, we examine whether transferred donor natural regulatory CD4 T cells (nT‐regs) inhibit host alloimmunity and prolong allograft survival.

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Publication: Frontiers in Immunology

Jacqueline H. Y. Siu, Veena Surendrakumar, James A. Richards and Gavin J. Pettigrew

5 November 2018


Summary:

Transplantation is unusual in that T cells can recognize alloantigen by at least two distinct pathways: as intact MHC alloantigen on the surface of donor cells via the direct pathway; and as self-restricted processed alloantigen via the indirect pathway. Direct pathway responses are viewed as strong but short-lived and hence responsible for acute rejection, whereas indirect pathway responses are typically thought to be much longer lasting and mediate the progression of chronic rejection. However, this is based on surprisingly scant experimental evidence, and the recent demonstration that MHC alloantigen can be re-presented intact on recipient dendritic cells—the semi-direct pathway—suggests that the conventional view may be an oversimplification.

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Publication: Biomaterials

Ng SS, Saeb-Parsy K, Blackford SJI, Segal JM, Serra MP, Horcas-Lopez M, No DY, Mastoridis S, Jassem W, Frank CW, Cho NJ, Nakauchi H, Glenn JS, Rashid ST. Biomaterials.

2018 Nov;182:299-311.

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Publication: Scientific Reports

Wang J, Ferreira R, Lu W, Farrow S, Downes K, Jermutus L, et al.

2018 Aug 13;8(1):12079

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Publication: Pediatric Nephrology

Martin JL, Gruszczyk AV, Beach TE, Murphy MP, Saeb-Parsy K.

2018 Jun 2.

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Publication: Journal of the American Heart Association

Kohlhauer M, Dawkins S, Costa ASH, Lee R, Young T, Pell VR, Choudhury RP, Banning AP, Kharbanda RK; Oxford Acute Myocardial Infarction (OxAMI) Study, Saeb-Parsy K, Murphy MP, Frezza C, Krieg T, Channon KM.

2018 Apr 6;7(8). pii: e007546

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Publication:

Jason M. Ali, Margaret C. Negus, Thomas M. Conlon, Ines G. Harper, M. Saeed Qureshi, Reza Motallebzadeh, Richard Willis, Kourosh Saeb-Parsy, Eleanor M. BoltonJ. Andrew Bradley, Gavin J. Pettigrew

9 February 2016


Summary:

MHC alloantigen is recognized by two pathways: “directly,” intact on donor cells, or “indirectly,” as self-restricted allopeptide. The duration of each pathway, and its relative contribution to allograft vasculopathy, remain unclear. Using a murine model of chronic allograft rejection, we report that direct-pathway CD4 T cell alloresponses, as well as indirect-pathway responses against MHC class II alloantigen, are curtailed by rapid elimination of donor hematopoietic antigen-presenting cells. In contrast, persistent presentation of epitope resulted in continual division and less-profound contraction of the class I allopeptide-specific CD4 T cell population, with approximately 10,000-fold more cells persisting than following acute allograft rejection. This expanded population nevertheless displayed sub-optimal anamnestic responses and was unable to provide co-stimulation-independent help for generating alloantibody. Indirect-pathway CD4 T cell responses are heterogeneous. Appreciation that responses against particular alloantigens dominate at late time points will likely inform development of strategies aimed at improving transplant outcomes.

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Publication: Nature

Norah M. E. Fogarty, Afshan McCarthy, Kirsten E. Snijders, Benjamin E. Powell, Nada Kubikova, Paul Blakeley, Rebecca Lea, Kay Elder, Sissy E. Wamaitha, Daesik Kim, Valdone Maciulyte, Jens Kleinjung, Jin-Soo Kim, Dagan Wells, Ludovic Vallier, Alessandro Bertero10, James M. A. Turner & Kathy K. Niakan

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Publication: Diabetes Obes Metab

El-Khairi R, Vallier L. 2016 Sep;18 Suppl 1:23

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Publication: Am J Transplant

Watson CJ, Kosmoliaptsis V, Randle LV, Russell NK, Griffiths WJ, Davies S, Mergental H, Butler AJ. 2016;16(1):353-7.

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Publication: J Heart Lung Transplant

Dijke EI, Platt JL, Blair P, Clatworthy MR, Patel JK, Kfoury AG, Cascalho M. B . 2016: S1053-2498(16)01286-9

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Publication: Cell Reports

Harper IG, Ali JM, Harper SJ, Wlodek E, Alsughayyir J, Negus MC, Qureshi MS, Motalleb-Zadeh R, Saeb-Parsy K, Bolton EM, Bradley JA, Clatworthy MR, Conlon TM, Pettigrew GJ. 2016;15(6):1214-27

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Publication: Curr Transplant Rep

Castro-Dopico T and Clatworthy MR. 2016;3(4):284-293.

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Publication: Transpl Int

Amin I, Butler AJ, Defries G, Russell NK, Harper SJ, Jah A, Saeb-Parsy K, Pettigrew GJ, Watson CJ. 2017 Jan 21.

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Publication: Clin Transplant

Mah TJ, Mallon DH, Brewster O, Saeb-Parsy K, Butler AJ, Bradley JA, Kosmoliaptsis V. 2017 Jan 23.

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