Michael Uhlin's Group
T cells and their role in health, disease and as therapy
We focus our research on T lymphocytes and their protective role against various cancers and diseases. The research-group is composed of basic and clinical researchers with a common interest in how T lymphocytes function under normal conditions, and why their function is inhibited in tumor diseases or over-activated in autoimmune diseases. Part of the group's activity is associated with the Center for allogeneic stem cell transplantation (CAST) where we develop various T cell-based therapies against infections, rejection and malignant relapse. We also study how the immune system with a focus on how T lymphocytes regenerate after transplantation.
We also have a great interest in T lymphocyte function in patients with solid tumors such as prostate and ovarian cancer. Using flow cytometry and molecular biology we perform thorough characterization of the phenotype and function of lymphocytes in the tumor tissue.
When T lymphocytes are over-activated it can lead to localized or systemic autoimmunity. Together with the department of Dermatology at Södersjukhuset we are trying to elucidate immunological mechanisms involved in ectopic eczema.
Immunological development after allogeneic Stem cell transplantation
Early detection of acute GVHD
Graft-versus-host-disease (GvHD) is a common complication of HSCT, with a high morbidity and mortality rate in severe cases. The pathogenesis is caused by an attack of the donor immune cells on healthy recipient cells, particularly in the skin, liver and gastrointestinal tract. GvHD is seen in an acute and chronic type, where by definition the acute type develops within 3 months after transplantation. Unfortunately, at the moment there are very few markers that can predict an increased risk for acute GvHD in patients.
In our group we are working on a method which will hopefully enable early detection of acute GVHD after HSCT. We are collecting samples of patient and donor pairs before HSCT. These cells are used against each other in different immunological tests. The results are then correlated to certain important parameters, such as acute GVHD, after transplantation. The objective is to seek out a prediction marker already before transplantation which may enable us to predict acute GVHD or even allow us to choose between donors. This in turn could lead to improved post-transplant treatment for patients.
Diagnostic marker for chronic GVHD
Another common complication after HSCT is chronic GvHD. Depending on the symptoms, chronic GvHD can range from a mild to a severe type, of which the severe type has a very high morbidity rate. Similarly as for acute GvHD, no clear predictive markers have yet been identified for the development of severe chronic GvHD, neither is the pathogenesis of chronic GvHD been elucidated.
We aim to shed a light on the pathogenesis of chronic GvHD by means of an extensive analysis of phenotypic and functional differences between patients with and without chronic GvHD. We hope to thus gain information on possible markers that could explain why some patients develop chronic GvHD and others do not. Increased knowledge of chronic GvHD would greatly improve post-transplant treatment for many individuals and thus increase patient welfare.
Long-term stable mixed chimerism
After HSCT, the recipient usually adopts the donor hematopoietic system and develops full donor chimerism (DC). However, in some cases, recipient hematopoietic cells remain and the patient instead develops mixed chimerism (MC). Several cases are known where stable mixed chimeras are in good health post-HSCT, even for a prolonged time. In this project we try to identify differences between donor and recipient immune systems in individuals with MC as well as identify immune phenotype differences between DC and MC patients.
Due to fear of relapse or rejection, MC patients have historically often been induced to DC by donor lymphocyte infusions (DLIs). As DLIs increases the risk of GvHD, results from this study could therefore improve post-HSCT treatment for patients in the future as well as give insight into the mechanisms behind MC.
Treatment of opportunistic infections
Several viral infections e.g. CMV, EBV and adenovirus can be life threatening after HSCT. EBV can even in some cases cause cancer, EBV lymphoma, which is a very severe complication and associated with a high rate of mortality. T cells specific for the EBV virus from the original donor is often an effective treatment of EBV lymphoma. We have developed a novel method for efficiently separating out specific T cells that only kill EBV-infected cells. Similarly, we have treated patients with severe CMV infection not responding to conventional therapy.
We are now isolating EBV-specific T cells from patient's parents or siblings of a patient developing EBV lymphoma after transplantation. We now produce these cells within one day. We will also produce T cells that can kill CMV virus, either from the original donor or relatives, and treat patients who do not respond to usual treatment or where the situation is life threatening. Treatment may be by extension also be used to treat severe viral diseases in other patients.
T cell inhibition in Solid tumors
In our group, we also have projects focusing on tumor-infiltrating lymphocytes (TILs) in solid tumors. Currently we are working with human ovarian cancer and prostate cancer. We have developed a method in which we process tumor tissue without using enzymes or incubation, and obtain lymphocytes in a single cell suspension. Thereafter, we perform characterization of the lymphocytes by flow cytometry and also perform cytokine analysis. In both cancer types, we compare the phenotype of lymphocytes from multiple tissues within the same patient aiming to increase our understanding of how the tumor environment can alter the phenotype of TILs and their ability to function and eliminate tumor cells. Suppression of immune reactivity by increased expression of co-inhibitory receptors has been discussed as a major reason to why the immune system fails to control tumor development. Better understanding of the interactions between the immune system and cancer can potentially be used to predict prognosis, clinical outcome and help to develop effective immunotherapy treatments.
Gamma-Delta T cells as adoptive cell therapy and their development after allogeneic stem cell transplantation
T cells expressing a γδ T cell receptor are unique to humans and higher primates, and differ fundamentally from conventional αβ T cells. The γδ T cell subset usually only comprises 1–5% of circulating T cells but during particular bacterial and viral infections they can expand, in extreme cases up to 50 %. γδ T cells can be activated in an MHC independent fashion as well as via NK cell receptors and TLR receptors making them a cell group on the border of innate and adaptive immunity. Recently, studies have evaluated the potency of γδ T cells as cancer-therapy
After HSCT, increased frequencies and function of γδ T cells in transplanted patients are associated with a protective role against Cytomegalovirus (CMV) reactivation and disease. This is in agreement with several studies that have shown expansion and cytotoxic function of CMV-reactive γδ T cells in the peripheral blood of patients receiving renal and lung transplantations7.
Several observations have also shown that patients who develop increased numbers of donor-derived γδ T cells following haploidentical or partially mismatched HSCT have a significant increased leukemia-free survival (LFS) and overall survival (OS).
In theory, γδ T cells may provide an excellent T cell immunotherapy strategy for leukemia after HSCT, as the cells exhibit biologic characteristics consistent with innate immune cells allowing them to act in response to malignancies without recognition of alloantigens that could result in unwanted GVHD.
The goal of the project is to investigate the use of γδ T cells in therapy and the correlation between γδ T cell development after HSCT and malignant relapse.
Immunological mechanisms behind atopic eczema
Atopic dermatitis (AD) is the most common chronic inflammatory condition of the skin and the incidence has risen steadily the past 10 years. The symptoms usually appear before the age of two, affecting 15-30% of all children in the Western world, and up to one-third have continuing symptoms into adulthood.
In a subgroup of these patients immunological dysregulation is the root cause. Identification of these individuals may enable early and targeted onset of treatment action.
We study the phenotype of immune cells, their mutual assembly and activation degree in samples from inflamed and healthy skin from the same individual before and after treatment, and comparing this with healthy individuals.
To identify a specific reaction pattern may help in developing more individualized treatment options.
Alpha/beta T-cell depleted grafts as an immunological booster to treat graft failure after hematopoietic stem cell transplantation with HLA-matched related and unrelated donors.
J Immunol Res 2014 ;2014():578741
Novel method to characterize immune cells from human prostate tissue.
Prostate 2014 Oct;74(14):1391-9
T-cell receptor excision circle levels after allogeneic stem cell transplantation are predictive of relapse in patients with acute myeloid leukemia and myelodysplastic syndrome.
Stem Cells Dev. 2014 Jul;23(14):1559-67
Cord blood T cells cultured with IL-7 in addition to IL-2 exhibit a higher degree of polyfunctionality and superior proliferation potential.
J. Immunother. 2013 Oct;36(8):432-41
Rapid salvage treatment with virus-specific T cells for therapy-resistant disease.
Clin. Infect. Dis. 2012 Oct;55(8):1064-73
Mesenchymal stem cells inhibit thymic reconstitution after allogeneic cord blood transplantation.
Stem Cells Dev. 2012 Jun;21(9):1409-17
Expansion of T-cells from the cord blood graft as a predictive tool for complications and outcome of cord blood transplantation.
Clin. Immunol. 2012 May;143(2):134-44
Clinical expansion of cord blood-derived T cells for use as donor lymphocyte infusion after cord blood transplantation.
J. Immunother. 2010 Jan;33(1):96-105
A novel haplo-identical adoptive CTL therapy as a treatment for EBV-associated lymphoma after stem cell transplantation.
Cancer Immunol. Immunother. 2010 Mar;59(3):473-7