Immune reconstitution in rheumatic disease patients after autologous hematopoietic stem cell transplantation.

High-dose conditioning chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) in systemic sclerosis (SSc), lupus erythematosus (SLE), juvenile idiopathic arthritis (JIA), or rheumatoid arthritis (RA) was shown to allow eradication of the abnormal autoimmune compartment and "resetting" of the immune response, all contributing to the observed clinical response. A subset of patients has less favorable clinical outcomes after transplant, as auto-reactive memory cells may escape depletion or the regulatory immune network renewal be incomplete. Conditioning permits non-specific abrogation of the autoreactive T- and B-cell responses and eliminates the autoimmune repertoire. Re-infusion of autologous hematopoietic stem cells shortens the leucopenia duration and contributes to both hematologic and immune reconstitutions. After engraftment and neutrophil recovery, the first phase of immune reconstitution is characterized by clonal expansion of residual memory lymphocytes in response to early antigen stimulation and/or lymphopenia-induced proliferation. Renewal of the immune repertoire follows through exportation of de novo generated thymic-derived naïve T cells and bone marrow-derived naïve B cells, expansion of the regulatory network, and a shift from a pro-inflammatory to a more auto-tolerant profile. We review the well-described mechanisms of immune resetting and their relative contribution to disease control according to the transplantation regimen and the underlying rheumatic diseases.

Reconstitution of the immune system and clinical correlates after stem cell transplantation for systemic sclerosis.

Systemic sclerosis (SSc) is a chronic autoimmune disease that includes fibrosis, diffuse vasculopathy, inflammation, and autoimmunity. Autologous hematopoietic stem cell transplantation (auto-HSCT) is considered for patients with severe and progressive SSc. In recent decades, knowledge about patient management and clinical outcomes after auto-HSCT has significantly improved. Mechanistic studies have contributed to increasing the comprehension of how profound and long-lasting are the modifications to the immune system induced by transplantation. This review revisits the immune monitoring studies after auto-HSCT for SSc patients and how they relate to clinical outcomes. This understanding is essential to further improve clinical applications of auto-HSCT and enhance patient outcomes.

Monitoring the responsiveness of T and antigen presenting cell compartments in breast cancer patients is useful to predict clinical tumor response to neoadjuvant chemotherapy.

BACKGROUND: Vaccination of mice with tumors treated with Doxorubicin promotes a T cell immunity that relies on dendritic cell (DC) activation and is responsible for tumor control in vaccinated animals. Despite Doxorubicin in combination with Cyclophosphamide (A/C) is widely used to treat breast cancer patients, the stimulating effect of A/C on T and APC compartments and its correlation with patient's clinical response remains to be proved. METHODS: In this prospective study, we designed an in vitro system to monitor various immunological readouts in PBMCs obtained from a total of 17 breast cancer patients before, and after neoadjuvant anti-tumor therapy with A/C. RESULTS: The results show that before treatment, T cells and DCs, exhibit a marked unresponsiveness to in vitro stimulus: whereas T cells exhibit poor TCR internalization and limited expression of CD154 in response to anti-CD3/CD28/CD2 stimulation, DCs secrete low levels of IL-12p70 and limited CD83 expression in response to pro-inflammatory cytokines. Notably, after treatment the responsiveness of T and APC compartments was recovered, and furthermore, this recovery correlated with patients' residual cancer burden stage. CONCLUSIONS: Our results let us to argue that the model used here to monitor the T and APC compartments is suitable to survey the recovery of immune surveillance and to predict tumor response during A/C chemotherapy.

Inmunología del cáncer I: bases moleculares y celulares de la respuesta inmune antitumoral / Cancer immunology I: molecular and cellular bases of the antitumor immune response

Significativos recursos materiales, financieros y humanos se dedican a la investigación de la biología del cáncer. La validación de biomarcadores, el desarrollo de novedosos métodos para el diagnóstico y la terapia, la implementación de programas de pesquisa a nivel poblacional y la promoción de estilos de vida saludables han impactado positivamente en la prevención y control de este grupo de enfermedades. Sin embargo, el cáncer sigue siendo un problema de salud mundial, entre otros factores, por la compleja relación que se establece entre el sistema inmune del hospedero y las células neoplásicas. Está demostrado que los mecanismos efectores que posee el sistema inmune permiten detectar y eliminar las células transformadas. Sin embargo, estos mismos mecanismos promueven la evolución somática de los tumores, al seleccionar variantes celulares resistentes a la acción de la inmunidad. Esta interacción ocurre fundamentalmente en el microambiente tumoral y ha sido conceptualizada como inmunoedición tumoral. Lo anterior sustenta la racionalidad de la inmunoterapia, la que buscar reforzar la inmunidad antitumoral, a la vez que bloquea los mecanismos de evasión a la inmunovigilancia. Con este trabajo de revisión iniciamos una serie de tres artículos que, en este orden, recorrerán las bases moleculares y celulares de la respuesta inmune antitumoral, presentarán los fundamentos de la biología tumoral y, finalmente, abordarán las implicaciones de la compleja relación entre el sistema inmune y las neoplasias para la inmunoterapia en cáncer

Substantial material, financial and human resources are dedicated to research on tumor biology. The validation of biomarkers, the development of novel diagnostic and therapeutic methods, the implementation of early detection programs in communities, and the promotion of healthy lifestyles have positively impacted on the prevention and control of this group of diseases. However, cancer remains a global health problem, due to the complex relationship between the host immune system and the cancer cells. It is a fact that the immune system´s effector mechanisms enable the detection and elimination of cancer cells. However, these immune mechanisms also promote the somatic evolution of tumors by selecting cellular clones resistant to immunity. This complex relationship conceptualized as cancer immunoediting develops mainly at the tumor microenvironment. Immunotherapy approaches are designed to reinforce antitumor immunity, while blocking immune escape mechanisms. This review starts a series of three articles that are going to review the molecular and cellular bases of the antitumor immune response, present the bases of tumor biology and, finally, address the implications of the complex relationship between the immune system and neoplasias for cancer immunotherapy