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
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.View publication
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
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).View publication
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
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.View publication
Publication: BMJ Open
John OO Ayorinde, Dominic 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
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.View publication
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
The development of humoral autoimmunity following organ transplantation is increasingly recognised, but of uncertain significance. We examine whether autoimmunity contributes independently to allograft rejection.View publication
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†,
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.View publication
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
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.View publication
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
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.View publication
Publication: Frontiers in Immunology
Jacqueline H. Y. Siu, Veena Surendrakumar, James A. Richards and Gavin J. Pettigrew
5 November 2018
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.View publication
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.View publication
Publication: Scientific Reports
Wang J, Ferreira R, Lu W, Farrow S, Downes K, Jermutus L, et al.
2018 Aug 13;8(1):12079View publication
Publication: Pediatric Nephrology
Martin JL, Gruszczyk AV, Beach TE, Murphy MP, Saeb-Parsy K.
2018 Jun 2.View publication
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: e007546View 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. Bolton, J. Andrew Bradley, Gavin J. Pettigrew
9 February 2016
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.View publication
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. NiakanView publication
Publication: Diabetes Obes Metab
El-Khairi R, Vallier L. 2016 Sep;18 Suppl 1:23View publication
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.View publication
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):1214-27View publication
Publication: Curr Opin Organ Transplant
Inaba A, Clatworthy MR. 2016;21(4):419-26View publication
Publication: Am J Transplant
Kosmoliaptsis V, Mallon DH, Chen Y, Bolton EM, Bradley JA, Taylor CJ. 2016 Jul;16(7):2139-47View publication
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.View publication
Publication: Clin Transplant
Mah TJ, Mallon DH, Brewster O, Saeb-Parsy K, Butler AJ, Bradley JA, Kosmoliaptsis V. 2017 Jan 23.View publication
Mirshekar-Syahkal B, Summers D, Bradbury LL, Aly M, Bardsley V, Berry M, Norris JM, Torpey N, Clatworthy MR, Bradley JA, Pettigrew GJ. Local Expansion of Donation After Circulatory Death Kidney Transplant Activity Improves Waitlisted Outcomes and Addresses Inequities of Access to Transplantation. Am J Transplant. 2017 Feb;17(2):390-400. DOI: 10.1111/ajt.13968View publication