Immune Reconstitution

Research Interests

I am interested on studying the web of relationships and interdependencies the immune system undertakes. I have been at first studying how B cells and immunoglobulin influence T cell development in the thymus promoting T cell receptor diversification and lymphocyte repertoire shaping and how can that be used to modulate peripheral T cell function. Recently, I have projects examining the role of immunoglobulin as a promoter of a better and faster immune reconstitution. Also, I am developing translational studies that apply to the clinical field the basic research I have been conducting. In this sense, I am studying the effect of B cell depletion, resulted by treatment with biological therapies against B cells, on the immune system.
In general, my areas of interests are mainly how to apply fundamental immunological concepts and discoveries to the clinical field, mostly to hematological malignancies and treatment options. Other areas of scientific research are pathogenesis of lymphoid malignancies, immunological responses to cancer and modulation of biological treatments.

Group Members

Research Project

Immune recovery after Autologous Stem Cell Transplantation - modulation by Ig and potential clinical application

In spite of the increased survival and cure rates obtained by conventional chemotherapy for non-Hodgkin’s lymphoma (NHL), once relapsed, the probability of cure is less than 20%. Autologous stem cell transplantation (ASCT) has been shown to be superior to salvage chemotherapy in prolonging survival of patients with relapsed, chemo-sensitive aggressive NHL. However, post-transplant relapse rates still range between 40% to 70%. The observed relapse rate after ASCT is attributed to the failure of the high-dose chemotherapy in fully eradicating residual lymphoma and to the lack of graft versus tumor effect observed in allogeneic stem cell transplantation (allo-SCT). Thus, one possible way to improve the clinical outcomes following ASCT is to attempt to mimic the anti-tumor efficacy of graft versus lymphoma effect of allo-SCT by facilitating early immune reconstitution. Post-ASCT immune-recovery studies have shown that T and B cell functions are not fully recovered during the period in which most lymphomas recurrences are detected. A faster reconstitution of numbers and function of anti-tumor elements of the immune system may allow a more efficient eradication of the residual tumor. We have recently reported that the absolute lymphocyte count (ALC), as a surrogate marker of immune recovery, at day 15 post-ASCT is a powerful prognostic factor for survival in NHL. The superior clinical outcome observed in ASCT with an ALC > 500 cells/ml at day 15 is explained by the fact that the immune system may protect against minimal residual progression post-ASCT, similar to the graft versus tumor effect seen in the allogeneic stem cell transplantation setting. Likewise, our work has revealed that polyclonal immunoglobulin (Ig) may contribute diversity of the T cell repertoire, which in turn has been related to increased T cell-mediated immunity. Thus, we propose to define the role of specific therapeutic strategies using immunoglobulin to enhance immunity after autologous transplantation. Experiments are focused on the effect of the infusion of immunoglobulin and immunoglobulin derivatives in optimally promoting immune reconstitution. Understanding the function of immunoglobulin in T cell immune reconstitution following ASCT in vivo will potentially create an opportunity to modulate this process in patients after ASCT (e.g. intravenous immunoglobulin therapy or IVIG derivative products) and to facilitate post-ASCT T cell immune recovery.

Funding

Fundação para a Ciência e a Tecnologia (FCT), Portugal

Associação Portuguesa contra a Leucemia, APCL, Portugal

Collaborators

Mayo Clinic, USA
Luis Porrata
Svetomir Markovic

Hôpital Pitié-Salpétrière, France
Adrien Six

FCUL, Portugal
Salomé Cabral

IPO, Portugal
Maria Gomes da Silva
José Cabeçadas

IGC, Portugal
Constantin Fesel

Research Project

B cell modulation of T cells function and repertoire - immune characterization of lymphoma patients receiving chemotherapy with or without a B cell depletion agent

Patients with different lymphoma types are frequently treated with combination chemotherapy together with a biological agent that depletes neoplastic and normal B cells, the monoclonal antibody anti CD 20 Rituximab. The combination of Rituximab with chemotherapy has been increasingly used during the last years, since it has been demonstrated that it leads to favorable clinical outcomes (higher response rates, duration of responses and even overall survival than chemotherapy alone) in the most frequent B cell lymphoma types, both when used at diagnosis and at relapse. However, immune reconstitution after treatment with rituximab is not yet well characterized in the literature. It is known that patients receiving rituximab and chemotherapy suffer prolonged immunossupression that remains for long periods after the end of the treatment. Peripheral B cell counts do not normalize before 6 to 9 months after Rituximab treatment. While not universally demonstrated, some authors have shown persistent hypogammaglobulinemia in certain patients’ subgroups. Not unexpectedly, patients under Rituximab, particularly when combined with cytotoxic drugs known to profoundly suppress the immune system, may present a different pattern of infections when compared to patients which treatment does not included this agent. Our recent work has shown that lack of B cells and immunoglobulin affects in vivo T cell immunity, both in terms of development of new T cells and of T cell function. The superior function of T cell in the presence of polyclonal immunoglobulin seems to be due to the highly diverse nature of the immunoglobulin molecule, which allows a wider repertoire of T cells to be selected in the thymus and, possibly, maintained at the periphery. Thus, in addition to its other properties, the use of immunoglobulin emerges as a way to improve immune reconstitution, providing to conditions for the development a wider repertoire of T and B cells. If this is the case, the use of rituximab may have important implications in the immunity of the individuals receiving this agent, besides the anti lymphoma effects. The characterization of T cell immunity in individuals being intentionally depleted of B cells, as it is the case of B cell lymphoma patients treated with rituximab, is not known. Since these patients frequently receive myelossupressive chemotherapy at the same time, the effects of Rituximab can only be fully understood if patients under chemotherapy alone are compared with patients receiving the combined, chemo-immunotherapy regimens and, ideally, with patients receiving Rituximab alone. Knowledge on this area may impact to the current discussion of administering prolonged, maintenance treatment with rituximab in patients with certain types of B cell lymphoma. Here we propose a translational, longitudinal study aiming to examine and compare the impact of B cell depletion, and consequently of immunoglobulin depletion, on the T cell immunity in a 3 cohort of patients with B cell lymphoma who will be treated with:
1. Rituximab combined with chemotherapy;
2. Rituximab alone;
3. Chemotherapy alone.

For this, we propose to prospectively investigate several immunological parameters allowing a wide characterization of the patients’ immunity and a comparison of its status before and at several time points after treatment with rituximab, chemotherapy or both. All these immunological parameters will be correlated to clinical data retrieved from the clinical records of the 3 groups, namely, type and severity of infections, time to progression/relapse, and overall and disease-specific survival. In our hospital, the number of new adult patients diagnosed with B cell lymphoma per year allows the development of the proposed study in the time frame of this project grant. The success of this study and the understanding of the effect of B cell depletion in the immune biology of B cell lymphoma patients will potentially create an opportunity to intervene and protect these patients from the undesired effects of secondary immunodeficiency.

Funding

Associação Portuguesa contra a Leucemia, APCL, Portugal

Collaborators

IPO, Portugal
Maria Gomes da Silva
Paula Gameiro da Costa
José Cabeçadas

IGC, Portugal
Constantin Fesel

Publications

Pires, AE, Borges, C, Simões, F, Amorim, IR, Petrucci-Fonseca, F, Matos, J. (2009). Molecular Markers from domestic dog Y-chromosome discriminate Iberian wolves from domestic dogs (submitted)

Borges, C., Simoes, F. Fonseca, F.P., Matos, J & Pires, A.E. (2009). A multiplex snapshot assay for detection of Y-chromosome SNPs in dogs and the Iberian wolves Archivos de Zootecnia 58 (Supl. 1) :(in press)

Pires, AE, Amorim, IR, Ginja, C, Gomes, M, Godinho, I, Simões, F, Oom, M, Petrucci-Fonseca, F, Matos, J & Bruford, MW. (2009). Molecular Structure in peripheral dog breeds: Portuguese native breeds as a case study Animal Genetics 40 :383–392

João, C., Farinha P., Gomes da Silva M., Martins C., Crespo M., Cabeçadas J. (2007). MALT1 gene rearrangement is uncommon in primary breast MALT lymphomas Histopathology 50 :217-224

João, C. (2007). Immunoglobulin is a highly diverse self molecule that improves cellular diversity and function during immune reconstitution Medical Hypotheses 68 :158-161

João, C. Brenda M. Ogle, Susan Geyer (2006). Immunoglobulin promotes the diversity and the function of T cells European Journal of Immunology 36 :1718-1728

João, C., Luis F. Porrata, David J. Inwards, Stephen Ansell, Ivana Micallef, Patrick Johnston, Dennis A. Gastineau, Svetomir N. Markovic (2006). Early lymphocyte recovery after autologous stem cell transplantation predicts superior survival in Mantle Cell Lymphoma Bone Marrow Transplantation 37 :865-871

Pires, AE (2006). Phylogeny, Population Structure and Genetic Diversity of dog breeds in the Iberian Peninsula and North Africa, Doctoral Thesis Sciences Faculty, University of Lisbon and Cardiff University, School

Pires, AE, Ouragh, L, Kalboussi, M, Petrucci-Fonseca, F & Bruford, MW. (2006). Mitochondrial DNA variation and the relationships among Iberian and North African dog breeds Journal of Heredity 97 :318-330

João, C., Ogle B., Gay-Rabinstein C., Platt J. L., Cascalho M. (2004). B cell-dependent TCR diversification Journal of Immunology 172 :4709-4716

Ogle B., Cascalho M., João, C., Taylor W., West J. L., Platt L. J. (2003). Direct measurement of lymphocyte receptor diversity Nucleic Acids Research 31 :e139

Pires, AE & Fernandes, M (2003). Last lynxes in Portugal? Molecular approaches in a pre-extiction scenario Conservation Genetics 4 :525-532

João, C., Carrilho C., Leite A., Miranda C., Serra I., Reves L., Brandao T., Freitas P. (2001). Advantageous use of thorax x-ray for the localization of pneumothoraces in ventilated patients Revista Portuguesa Medicina Intensiva 2 :201-02 Link

João, C., Matias T., Sá J. (2001). Paget’s disease associated with myelofibrosis and myeloid metaplasia – a common pathophysiology? Haematologica 86 :E22 Link