UCL Cancer Institute

Transplantation Immunology Group


Group Leader: Dr Ronjon Chakraverty






Introduction to the Transplant Immunology Group

The Transplantation Immunology Group is based at the Hampstead Campus and forms part of a large Immunotherapy Programme at UCL. Our research involves both pre-clinical, translational and phase I/II projects that aim to develop innovative strategies to improve the anti-tumour effects of blood and bone marrow transplantation. We work closely with the groups of Professor Hans Stauss/Dr. Emma Morris (Tumour Immunology, Cellular and Gene Therapy), and Dr. Clare Bennett (Dendritic Cell Immunotherapy), with a number of fellows or PhD students working on joint projects.



Transplantation Immunology Group

  The Transplantation Immunology Group



Research

Following blood or bone marrow transplantation, donor T cells that have been infused as part of the graft or given at a later time point, become activated in response to antigenic differences between the donor and the recipient. This effect can be co-opted to generate anti-tumour activity, an effect termed the ‘graft-versus-tumour’ (GVT) response (Figure 1). Alternatively, donor T cells may react against normal tissues, leading to graft-versus-host disease (GVHD, Figure 2).

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 Fig 1 The Graft-versus-Leukaemia Response

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 Fig 2 Two photon imaging of GFP-expressing donor T cells in recipient skin following BMT and development of GVHD. Left image shows infiltration of GFP+ cells near hair follicles (arrow). Summary graph of infiltration compared to recipient without GVHD. Right graph shows rolling/adherent T cells within the post-capillary venule of the skin.


These outcomes depend upon how donor T cells recognize antigen and this, in turn is influenced by nature of the cells presenting antigen (Figure 3). We are interested in how distinct non-haematopoietic and haematopoietic cell populations in the recipient influence the development of donor T cell immunity after transplantation. This research offers the opportunity to develop new approaches to manipulating antigen presentation for therapeutic benefit e.g. following vaccination.

Ultimately, durable anti-tumour immunity requires that T cells with anti-tumour reactivity engraft and then persist long-term in the recipient. By exploring clinically relevant models, we are examining the mechanisms that influence the long-term survival of anti-tumour T cells such that they can provide long-term immune surveillance (Figure 4). An improved understanding of the pathways that regulate this property of ‘memory’ is helping us to engineer T cells that can maintain their functions over long periods.



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 Fig 3 Potential outcomes following donor T cell encounter with antigen-presenting cells within the recipient.

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 Fig 4 Transcriptional profiles of naïve transgenic T cells compared to effector cell populations which either contain or don’t contain memory precursor effector cells (MPEC) following activation by different antigen-presenting cell populations in vivo.




Current Research Projects

Pre-clinical:

  • The role of antigen presentation by the innate immune system in GVHD
  • The influence of co-inhibitory and co-stimulatory signalling in GVHD and GVL
  • The effect of antigen presentation by non-haematopoietic cells upon anti-tumour immunity
  • Tolerance pathways in dendritic cells
  • In vivo selection of anti-tumour T cells
  • Tumour targeting of anti-tumour cells
  • Memory programming of therapeutic T cells

Translational:

  • Selection of human memory T cells for clinical application
Phase I/II clinical studies:

  • ProT4; multi-centre randomised phase II study to evaluate the efficacy of prophylactic transfer of CD4 lymphocytes after T-cell depleted reduced intensity HLA-identical sibling transplantation for indolent non-Hodgkin’s lymphoma and CLL

 


Ronjon Chakraverty

Dr Ronjon Chakraverty

 



 

Group Members


•  Dr Barry Flutter (post-doctoral fellow)
•  Dr Pedro Velica (post-doctoral fellow)
•  Dr Sara Ghorashian (MRC Clinical Training Fellow)
•  Dr Ben Carpenter (MRC Clinical Training Fellow)
•  Dr James Griffin (Wellcome Clinical Training Fellow)
•  Janani Sivakumaran (PhD student)
•  Noha Edwards (PhD student)
•  Lei Zhang (Research Associate)

Collaborators


•  Dr Clare Bennett, UCL
•  Professor Hans Stauss/Dr Emma Morris, UCL
•  Dr Martin Pule, UCL
•  Professor Frederic Geissmann, KCL
•  Professor Megan Sykes, Columbia University, New York
•  Professor Gordon Freeman, Harvard Medical School, Boston

 



 

Selected Publications


1. Bennett C.L. , Fallah-Arani F., Conlan T., Trouillet C., Goold H., Chorro L., Flutter B., Means T.K., Geissmann F. and Chakraverty R. Langerhans Cells Regulate Cutaneous Injury by Licensing CD8 Effector Cells Recruited to the Skin. Blood 2011, 117:7063-9. Pubmed

2. Flutter B., Edwards N., Fallah-Arani F., Henderson S., Chai J-G, Sivakumaran S., Ghorashian S., Bennett C. L., Freeman G. J., Sykes M. and Chakraverty R. Non-hematopoietic antigen blocks memory programming of alloreactive CD8+ T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation. Journal of Clinical Investigation 2010, 120:3855-68. Pubmed

3. Chakraverty, R., G. Orti, M. Roughton, J. Shen, A. Fielding, P. Kottaridis, D. Milligan, M. Collin, C. Crawley, P. Johnson, A. Clark, A. Parker, A. Bloor, R. Pettengell, J. Snowden, A. Pettitt, R. Clark, G. Hale, K. Peggs, K. Thomson, E. Morris, and S. Mackinnon. Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD and immune reconstitution. Blood 2010, 116:3080-8. Pubmed

4. Orti, G., Lowdell M., Fielding A., Samuel E., Pang K., Kottaridis P., Morris E., Thomson K., Peggs K., Mackinnon S. and Chakraverty R. Phase I study of high-stringency CD8 depletion of donor leukocyte infusions after allogeneic hematopoietic stem cell transplantation. Transplantation 2009 88:1312-1318. Pubmed

5. Chakraverty R, Flutter B, Fallah-Arani F, Eom HS, Means T, Andreola G, Schwarte S, Buchli J, Cotter P, Zhao G, Sykes M. The host environment regulates the function of CD8+ graft-versus-host-reactive effector cells. Journal of Immunology 2008 181:6820-8. Pubmed

6. Chakraverty R., Eom H., Sachs J., Buchli J., Cotter P., Hsu R., Zhao G. and Sykes M. Host MHC Class II+ antigen-presenting cells and CD4 cells are required for CD8-dependent graft-versus-leukemia responses following delayed donor leukocyte infusions. Blood 2006 108:2106-2113. Pubmed

7. Chakraverty R., Côté D., Buchli J., Cotter P., Hsu R., Zhao G., Sachs T., Pitsillides C.M., Bronson R., Means T., Lin C. and Sykes M. An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues. Journal of Experimental Medicine 2006 2003: 2021-2031. Pubmed

8. Freeman L., Hewison M., Hughes S., Evans K., Hardie D., Means T. and Chakraverty R. Expression of 11beta-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells. Blood 2005 106:2042-9. Pubmed