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Lombardi Group

Our interest is in immunoregulation and in particularly in the biology and clinical translation of regulatory T cells in preventing graft rejection and cure autoimmune diseases or any other inflammatory situation.

Members

Giovanna Lombardi

Giovanna Lombardi

Professor of Human Transplant Immunology

Researcher looking into microscope

Genetic engineering of Tregs to further improve their function in preventing transplant rejection

Human Tregs have been transduced with a lentiviral vectosr containing a chimeric antigen receptor (CAR) specific for an HLA class I molecule expressed by the transplant. We have shown that in vivo CAR-Tregs were superior compared to polyclonal Tregs. To further improve the function of the Tregs, the construct containing the CAR has been further manipulated to contain: 1. An additional gene encoding for IL-10; and 2. The CD28 co-stimulatory endodomain has been substituted with genes encoding for other molecules such as OX-40, 4-1BB, CD27, ICOS and death receptor 3 (DR3). The different constructs have been generated, Tregs have been transduced and the initial tests have been performed in vitro. Their function in vitro and then in vivo needs to be evaluated using suppression assays and humanised mouse models, respectively.

Close up of microscope

Understanding the origin and function of a new Treg population identified in the thymus

Tregs are generated in the thymus. It is now broadly accepted that Tregs are very heterogenous. We have studied the distribution of Treg subpopulation in circulation and tissues (including thymus). We have identified a subpopulation expressing CD161 and we have further analysed the distribution and function of Th-like Tregs. More recently we have identified a subpopulation in the thymus characterised by the expression of molecules such as ICOS. However the origin and function of this Treg population need to be defined. Answering these questions not only will improve our understanding of Treg biology but also will help in designing future Treg product for the treatment of children receiving heart transplants. In these children the thymus is removed at the time of surgery and can be used as the source of Tregs for clinical application.

Scientist using a pipette

Combination therapies for the prevention of transplant rejection

Treg therapy in patients receiving kidney and renal transplants has been shown to be safe with a hint of efficacy. However, it is clear that Tregs may be not enough to induce transplantation tolerance. Combining the Treg treatment with other therapies may be the way forward. We have just completed a study in which we have demonstrated that perfusing the organ with anti-thrombin agent at the time of transplantation with Treg infusion further delay transplant rejection in a preclinical model of hear transplantation. We are now planning to investigate whether in patients that are sensitised to alloantigens due to previous transplants would be an advantage to combine B cell depletion with Treg therapy.

Scientist using pipette

Immunogenicity test platform - in vitro and in vivo

Human embryonic (hES) and pluripotent stem cells (iPSCs)-derived cells can be used as unlimited renewable source for cell therapy targeted to treat several diseases. Once transplanted in patients, particularly if they are allogeneic to the recipient, the main challenge is represented by the immune rejection, namely the activation of the innate and adaptive immunity leading to cell loss. The immunogenicity of these products is still not fully understood hence we have focussed on, hES- and iPSC-derived hepatocytes to develop an immunological platform in vitro useful for testing the immunogenicity of different hES and iPSCs products. We found that these cells express MHC class I molecules (HLA-ABC) while co-stimulatory molecules (CD86, CD80, CD40) and MHC class II molecules (HLA-DR) are absent. Both hES- and iPSC-derived hepatocytes are not immunogenic and show an immunoregolatory capacity in vitro. The next step is to evaluate their immunogeneicity in vivo in pre-clinical models.

Scientist handling tube

Study of Treg cell biology and their clinical application in the treatment of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex and poorly understood autoimmune disease. The disease harms multiple tissues and organs. Although different treatments are available, none are curative, and relapses of the disease remain common. The analysis of Treg cells in patients with SLE shows that they are dysfunctional and one of the factors behind the exaggerated inflammatory response. We have developed a protocol to ex-vivo expand and restore the function of SLE-Tregs. This study aims to investigate whether the production of a functional and stable clinical SLE-Treg-product can be used in a program of cell therapy. We are currently: 1. Characterising SLE-Tregs before and after ex-vivo expansion to correlate the defective function with molecular markers that can be used as diagnostic tool. 2. Collecting data to apply for ethical and regulatory (MHRA) approval to evaluate the safety and efficacy of Tregs in the treatment of patients with SLE.

arteries

Study of the role of Treg cells in the development of atherosclerosis

Cardiovascular disease (CVD) is a leading cause of mortality worldwide. Atherosclerosis, the most common cause of cardiovascular disease is characterised by slow progressing chronic inflammation resulting in accumulation of lipid-laden plaques in large and medium arteries. In CVD, Tregs have been observed to be less abundant and less functional. There are several key aspects of the atherosclerotic micro-environment including hyperlipidaemia and the presence of increased oxidative stress that can be responsible for the dysfunction of Tregs in CVD. The aim of the project is to longitudinally analyse the distribution of Treg-subsets and other components of the immune system in patients with high level of cholesterol. The study wants to investigate the effect of oxidative stress on self-antigens and their capacity to activate an inflammatory response leading to atherosclerosis. The results want to identify new antigenic targets to develop a programme of vaccination in patients with high level of cholesterol.

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Our partners

MRC new logo

Medical Research Council

Lupus UK

Lupus UK

BHF

British Heart Foundation

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Guy's and St Thomas' NHS Foundation Trust

NIHR Guy's and St Thomas' Biomedical Research Centre logo

NIHR Guy's and St Thomas' Biomedical Research Centre

Rosetrees Trust logo

Rosetrees Trust

Group lead

Giovanna Lombardi 160 x 160 profile

Professor Giovanna Lombardi

Professor of Human Transplant Immunology

Contact us

020 71887674