Inmunidad y terapia génica: beneficios y riesgos / Immunity and gene therapy: benefits and risks

Las inmunodeficiencias (ID) congénitas son desafortunados experimentos de la Naturaleza que afectan a la inmunidad. Resulta especialmente apropiado que puedan curarse mediante afortunados experimentos diseñados por el ser humano. Ya fue así en 1968, cuando una ID ligada al cromosoma X se convirtió en la primera enfermedad humana curada con éxito por trasplante de médula ósea, un procedimiento terapéutico que ahora es estándar para muchas otras patologías incluida el cáncer. Naturalmente, se observaron efectos adversos graves como la enfermedad del injerto contra el huésped. Más de 30 años después, la misma ID ha sido la primera en ser curada por terapia génica. Hay obstáculos que superar, como ha demostrado la leucemia de células T desarrollada por oncogénesis insercional en dos pacientes. La propia inmunidad puede ser un obstáculo para la terapia génica cuando se dirige contra el vector o incluso la proteína terapéutica. Pero la terapia génica seguirá adelante. El cáncer, las enfermedades infecciosas incluido el Sindrome de la Inmunodeficiencia Adquirida (SIDA), y otras enfermedades congénitas son las siguientes de la lista. Los beneficios globales serán probablemente más que los riesgos, como se demostró para el trasplante (AU)

Toward gene therapy for human CD3 deficiencies.

The CD3 subunits of the T cell receptor-CD3 complex (TCR-CD3) help to regulate surface TCR-CD3 expression, and participate in signal transduction leading to intrathymic selection and peripheral antigen recognition by T lymphocytes. Humans who lack individual CD3 chains show impairments in the expression and activation-induced downregulation of TCR-CD3, and the defective immune responses that result may be lethal. We have investigated delivery of a normal CD3 chain to treat disorders of this type. Retroviral transduction of CD3gamma into CD3gamma-deficient peripheral blood T lymphocytes from two unrelated patients selectively corrected the observed TCR-CD3 expression and downregulation defects, but unexpectedly seemed to cause adverse effects that can be explained by an autoreactive recognition mechanism. These data support the feasibility of gene therapy for human CD3 deficiencies, but also suggest that gene transfer into postthymic lymphocytes carrying mutations on T cell recognition or activation pathways may disrupt their intrathymic calibration and become harmful to the host.

Characterization of Herpesvirus saimiri-transformed T lymphocytes from common variable immunodeficiency patients.

Common variable immunodeficiency (CVID) is a very frequent but heterogeneous syndrome of antibody formation. The primary defect remains unknown, but many reports describe peripheral blood T lymphocyte dysfunctions in a substantial proportion of CVID patients, which may impair T--B cell collaboration. In order to investigate whether such putative defects were intrinsic to T cells or, rather, secondary to quantitative differences in T cell subset distribution, or to other described disorders, we have used Herpesvirus saimiri (HVS) for the targeted transformation of CVID CD4+ and CD8+ T cells and subsequent functional evaluation by flow cytometry of their capacity to generate cell surface (CD154, CD69) or soluble (IL-2, TNF-alpha, IFN-gamma) help after CD3 engagement. Unexpectedly, the results showed that 40 different CVID blood samples exposed to HVS gave rise with a significantly increased frequency to transformed CD4+ T cell lines, compared to 40 age-matched controls (27% versus 3%, P < or = 0.00002) suggesting the existence of a CVID-specific signalling difference which affects CD4+ cell transformation efficiency. The functional analysis of 10 CD4+ and 15 CD8+ pure transformed T cell lines from CVID patients did not reveal any statistically significant difference as compared to controls. However, half of the CD4+ transformed cell lines showed CD154 (but not CD69) induction (mean value of 46.8%) under the lower limit of the normal controls (mean value of 82.4%, P < or = 0.0001). Exactly the same five cell lines showed, in addition, a significantly low induction of IL-2 (P < or = 0.04), but not of TNF-alpha or IFN-gamma. None of these differences were observed in the remaining CD4+ cell lines or in any of the transformed CD8+ cell lines. We conclude that certain CVID patients show selective and intrinsic impairments for the generation of cell surface and soluble help by CD4+ T cells, which may be relevant for B lymphocyte function. The transformed T cell lines will be useful to establish the biochemical mechanisms responsible for the described impairments.

Terapia génica in vitro de inmunodeficiencias linfoides y mieloides

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