01865 612273 (Monica Dolton – TRIG Research Project Manager)
BM BCh, MA (Oxon), D.Phil, MRCP (UK)
Clinical Lecturer in Renal Medicine
- Specialist Registrar in Renal and General (Internal) Medicine
My research focuses using markers in the immune system to predict outcomes in patients who have received a renal transplant. I am particularly focused on exploring the effect of ageing in the immune system on transplant outcomes.
A transplant is the most effective treatment for kidney failure. As a result, we are transplanting more and more people each year, worldwide. Because kidney disease is most common in older people, the average age of transplant recipients is increasing. Advances in recent years have significantly improved the short term outcome of patients who receive a transplant, but long-term outcomes remain modest. This is partly due to the medication that must be given to prevent the immune system attacking the transplant (‘immunosuppression’). Over time, this medication damages the transplant and makes patients more prone to infection and cancer.
We know that the immune system undergoes changes as we age as a result of long-term exposure to viruses and other factors in the environment. We refer to these changes as ‘immunosenescence’. Over time, this can lead to the immune system being less effective at protecting us from infection and less responsive to vaccination.
My work focuses on two aspects of immunosenescence in transplantation:
1) Patients who have had an organ transplant for many years are at increased risk of cancer, and in particular skin cancer. This is partly as a result of the medication given to prevent the body attacking the transplant (‘immunosuppression’). Work we have done previously has shown that patients with a long-term kidney transplant who shows signs of immunosenescence are more likely to develop skin cancer (Bottomley et al, J Am Soc Nephrol, 2016). We do not fully understand why this is.
To understand this in greater detail, we are looking at the immune cells from the blood of these patients to see how well they work. We are looking at the skin cancers removed from these patients to look at how the immune cells behave inside the cancer itself. We are interested in whether the cells from patients with immunosenescence behave differently to those patients who do not show signs of immunosenescence.
2) Following an organ transplant, patients must take immunosuppression to prevent the immune system attacking (rejecting) a transplant. Because of the side effects of taking these medications (such as infection and damage to the transplant), new treatments are being tested to reduce the need for these medications. One method in clinical trials is to use a type of cell called a regulatory T cell (‘Treg’), which are found naturally in our immune system. Models have shown that injecting extra Treg after a transplant can ‘educate’ the immune system to stop it attacking the new organ.
We do not know whether immunosenescence affects the body’s ability to reject a transplant or causes it to behave differently when we attempt to control the immune system, for example using immunosuppression or Treg.
We are collaborating with the research group of Professor Paul Klenerman of the Peter Medawar Building for Pathogen Research to develop a model of transplantation in the setting of immunosenescence, which will allow us to study these issues in more depth.
The work we are undertaking in this area may allow us to use the immune system in clinical practice in the future, to guide the type and amount of immunosuppression we give to transplant recipients. Being able to identify patients who may safely take less immunosuppression may reduce the problems encountered by patients partly as a result of these drugs, including cancer and infection.
Alongside my research, I continue to work clinically as a specialist registrar in renal medicine, working in the Oxford Kidney Unit at the Churchill Hospital.
The Role of the Immune System in Cutaneous Squamous Cell Carcinoma.
Bottomley MJ. et al, (2019), Int J Mol Sci, 20
PR3 vasculitis presenting with symptomatic splenic and renal infarction: a case report and literature review.
Bottomley MJ. et al, (2019), BMC Nephrol, 20
Impact of intrapatient variability (IPV) in tacrolimus trough levels on long-term renal transplant function: multicentre collaborative retrospective cohort study protocol.
Goldsmith PM. et al, (2017), BMJ Open, 7
Application of Operational Tolerance Signatures Are Limited by Variability and Type of Immunosuppression in Renal Transplant Recipients: A Cross-Sectional Study.
Bottomley MJ. et al, (2017), Transplant Direct, 3
CD8+ Immunosenescence Predicts Post-Transplant Cutaneous Squamous Cell Carcinoma in High-Risk Patients.
Bottomley MJ. et al, (2016), J Am Soc Nephrol, 27, 1505 - 1515