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En partant des derniers paragraphes de la cinquième parti du Discours de la Méthode, on a reconstitué la formulation cartésienne de la perception d’un autre moi. Les critères de l’usage du langage et de la plasticité du comportement ont été analysés à la lumière de l’idée d’une machine universelle et du test de Turing. On conclut de la faiblesse de l’argument cartésien sur l’irréductibilité de la pensée à un dispositif machinal. En tant qu’issue de la difficulté, on propose une révision de la façon cartésienne de caractérisation de la pensée à partir du concept d’expérience, tout en abandonnant le thème d’une perception interne incommunicable et intémoignable.

In dieser Arbeit wird die Selbstdarstellung der Phänomenologie als Wissenschaft der Weltkonstituierende transzendentale n Subjektivität, nach einer Erklärung über das, was wir die «Grundfrage» der Phänomenologie nennen, betrachtet. Diese Grundfrage ist die thematisierung des unerklärt Voraussetzung aller philosophischer und wissenschaftlicher Erkenntnis: die Vorgegebenheit einer Welt als Horizont für alle aktuelle oder mögliche Forschung. Die phänomenologischen Begriffe von «Reduktion», «Intentionalität» und «transzendentaler Subjektivität» sind dargestellt als Strecken für die Begrenzung des Feldes, in dem die Frage über die Welt nachfolgend bearbeitet und systematisch beantwortet sein könnte.

Dans un contrepoint polémique au livre de A. Damásio, L'Erreur de Descartes, nous soutenons: (a) que la thèse de l a «séparation» de l’âme et du corps permet, dans les écrits physiologiques de Descartes tels que le Traité de l'Homme, une réduction des fonctions végétative et sensitive aux processus mécaniques et naturels du corps humain; (b) que l'in troduction d'une âme dans le corps se justifie, chez Descartes, par l'impossibilité de rendre raison de la rationalité du comportement humain et de la conscience par les simples mécanismes physiologiques et la seule «disposition des organes». On montre, donc, que Descartes est, d'un côté, un des père s de la moderne approche neurologique qui est à l a base du livre de M. Damásio et, de l'autre, qu'il a vu d'avance une des limites d'une explication exclusivement neurologique de la complexité du comportement humain.

The cross-recognition of peptides by cytotoxic T lymphocytes is a key element in immunology and in particular in peptide based immunotherapy. Here we develop three-dimensional (3D) quantitative structure-activity relationships (QSARs) to predict cross-recognition by Melan-A-specific cytotoxic T lymphocytes of peptides bound to HLA A*0201 (hereafter referred to as HLA A2). First, we predict the structure of a set of self- and pathogen-derived peptides bound to HLA A2 using a previously developed ab initio structure prediction approach [Fagerberg et al., J. Mol. Biol., 521-46 (2006)]. Second, shape and electrostatic energy calculations are performed on a 3D grid to produce similarity matrices which are combined with a genetic neural network method [So et al., J. Med. Chem., 4347-59 (1997)] to generate 3D-QSAR models. The models are extensively validated using several different approaches. During the model generation, the leave-one-out cross-validated correlation coefficient (q (2)) is used as the fitness criterion and all obtained models are evaluated based on their q (2) values. Moreover, the best model obtained for a partitioned data set is evaluated by its correlation coefficient (r = 0.92 for the external test set). The physical relevance of all models is tested using a functional dependence analysis and the robustness of the models obtained for the entire data set is confirmed using y-randomization. Finally, the validated models are tested for their utility in the setting of rational peptide design: their ability to discriminate between peptides that only contain side chain substitutions in a single secondary anchor position is evaluated. In addition, the predicted cross-recognition of the mono-substituted peptides is confirmed experimentally in chromium-release assays. These results underline the utility of 3D-QSARs in peptide mimetic design and suggest that the properties of the unbound epitope are sufficient to capture most of the information to determine the cross-recognition.

This chapter shows how the reception of Hussserl’s thought in general and the Ideen in Portugal and Brazil began with Luis Cabral de Moncada’s reading of Husserl with regard to the philosophy of law and how Husserl’s phenomenological approach then spread throughout the Portuguese-speaking world and continues to the present day.

Neste artigo, argumento que o idealismo transcendental da fenomenologia de Husserl é compatível com um realismo metafísico. Não só desenvolvo um argumento acerca da tese da consistência entre as duas posições filosóficas, mas defendo também que essa a posição própria de Husserl. Consequentemente, apoio a minha interpretação numa hermenêutica de alguns dos textos mais importantes do próprio Husserl, onde ele discute directamente a questão.

En este documento, debato ampliamente sobre la fenomenologia de la intersubjetividad presentada por Husserl y por Sartre, centrandome en los conceptos de empatia y ser-para-otros. Contrariamente a la opinion mas comun, rechazo la objecion de solipsista dirigida a Husserl y sostengo que es la descripcion de Sartre la que da lugar a esa objecion, en la medida en que el describe la conciencia de otro sujeto como una forma de autoconocimiento como un "objeto" (para "otros"). Termino senalando algunas directrices para convertir el analisis de Husserl de la aprehension de otros sujetos en una fenomenologia de la comunicacion del mas alto nivel.

En este ensayo intento hablar de varias tesis de Husserl relativas al concepto de norma y de ciencia normativa. Confrontando a Husserl con la teoria de la norma de Wundt, con la tesis acerca de la justicia de Kelsen y con la afirmacion de Schmitt de que los conceptos modernos de pensamiento politico son conceptos teologicos secularizados, trato de mostrar lo que el pensamiento de Husserl tiene que decir acerca de todos estos temas. Finalmente, hablo de varios problemas acerca del propio concepto de norma a la luz de la distincion de Searle entre reglas regulativas y reglas constitutivas.

In dieser Arbeit werden die Thesen S. J. Becks über den kantischen Begriff von Ding-an-sich geprüft. Es sollen weder die zwei Doktrinen verglichen werden, noch die Punkte, in denen sie übereinstimmen, noch die Punkte, in denen sie sich voneinander entfernen. Basis-Voraussetzung ist mehr die Idee, dass es eine kantische Lehre des Ding-an-sich nicht gibt, sondern, dass es vielfältige divergente Tendenzen gibt in der Art, wie Kant das Problem bearbeitet. Die Auffassung Becks wird als ein Dialog mit denjenigen divergenten Tendenzen dargestellt, die in Kants Gedanken koexistieren, und dadurch eine Reflexion, die an die eigene innere Entwicklung der kritischen Philosophie gebunden ist. Die Originalität von Becks Auffassung liegt in seiner Entscheidung eine eng idealistische Interpretation der transzendentale Philosophie zu privilegieren und - infolgedessen - die theoretischen Nichtigkeit des Begriffs des Ding-an-sich zu behaupten, wenn die systematische Darstellung der kritischen Philosophie nach seinem einzigen, voraussichtlichen Prinzip unternommen wird: das Prinzip der ursprünglichen synthetischen Einheit der Apperzeption. Diese Arbeit wird in drei Teile geteilt. Im ersten Teil wird Becks These geprüft, ob in der Kritik des vorliegenden Begriffs des Ding-an-sich eine Bewilligung Kants an dem Dogmatismus liegt, die durch didaktische und pädagogische Gründe determiniert ist. Im zweiten Teil werden die Übe rprüfungen, die von der systematischen Darstellung der kritischen Philosophie bei den Doktrinen der transzendentalen ästhetik, der transzendentalen Analytik und dem Schematismus gemacht werden müssen, gezeigt, so wie die nachfolgenden änderungen vom Sinn der Affektion, Synthese und Subsumption. Letztlich, im dritten Teil wird dargelegt, dass die Entscheidung Becks für den Idealismus mit einigen Punkten von Kants Denken nicht übereinstimmt und deswegen von ihm abgelehnt werden müsste.

Invariant NKT cells (iNKT cells) recognize glycolipid Ags via an invariant TCR α-chain and play a central role in various immune responses. Although human CD4+ and CD4− iNKT cell subsets both produce Th1 cytokines, the CD4+ subset displays an enhanced ability to secrete Th2 cytokines and shows regulatory activity. We performed an ex vivo analysis of blood, liver, and tumor iNKT cells from patients with hepatocellular carcinoma and metastases from uveal melanoma or colon carcinoma. Frequencies of Vα24/Vβ11 iNKT cells were increased in tumors, especially in patients with hepatocellular carcinoma. The proportions of CD4+, double negative, and CD8α+ iNKT cell subsets in the blood of patients were similar to those of healthy donors. However, we consistently found that the proportion of CD4+ iNKT cells increased gradually from blood to liver to tumor. Furthermore, CD4+ iNKT cell clones generated from healthy donors were functionally distinct from their CD4− counterparts, exhibiting higher Th2 cytokine production and lower cytolytic activity. Thus, in the tumor microenvironment the iNKT cell repertoire is modified by the enrichment of CD4+ iNKT cells, a subset able to generate Th2 cytokines that can inhibit the expansion of tumor Ag-specific CD8+ T cells. Because CD4+ iNKT cells appear inefficient in tumor defense and may even favor tumor growth and recurrence, novel iNKT-targeted therapies should restore CD4− iNKT cells at the tumor site and specifically induce Th1 cytokine production from all iNKT cell subsets.

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Expression of the cancer/germ-line antigen NY-ESO-1 by tumors elicits spontaneous humoral and cellular immune responses in some cancer patients. Development of vaccines capable of stimulating such comprehensive immune responses is desirable. We have produced recombinant lentivectors directing the intracellular synthesis of NY-ESO-1 (rLV/ESO) and have analyzed the in vivo immune response elicited by this vector. Single injection of rLV/ESO into HLA-A2-transgenic mice elicited long-lasting B and T cell responses against NY-ESO-1. CD8+ T cells against the HLA-A2-restricted peptide NY-ESO-1(157-165) were readily detectable ex vivo and showed restricted TCR Vbeta usage. Moreover, rLV/ESO elicited a far greater anti-NY-ESO-1(157-165) CD8+ T cell response than peptide- or protein-based vaccines. Anti-NY-ESO-1 antibodies were rapidly induced after immunization and their detection preceded that of the antigen-specific CD8+ T cells. The rLV/ESO also induced CD4+ T cells. These cells played an essential role as their depletion completely abrogated B cell and CD8+ T cell responses against NY-ESO-1. The induced CD4+ T cells were primarily directed against a single NY-ESO-1 epitope spanning amino acids 81-100. Altogether, our study shows that rLV/ESO induces potent and comprehensive immune responses in vivo.

International audience; The inducible heat shock protein Hsp70 has been described as a tumour antigen being frequently overexpressed in tumours of various histologic origins, with a role in tumourigenicity, as a critical event in tumour progression. A strategy to enhance the immune response to an antigen is the identification of multiple epitopes and the induction of a polyspecific response. Applied to tumour vaccination, such a polyspecific response should lead to a more robust antitumour efficacy. The long peptide Hsp70380-402 encompasses three nonamer peptides with a high affinity for HLA-A *0201. In a previous paper, we have shown that two of these nonamer peptides, p391 and p393, can raise CTL to recognize tumour cells overexpressing Hsp70. In the present paper, we demonstrate that the third nonamer peptide, p380, is a new epitope efficient in raising an antitumour immune response. The p380-402 polypeptide was able to induce an immune response against each of the three constituent epitopes both in vivo in HLA-A *0201 transgenic mice and in vitro with human PBMC. This polypeptide therefore constitutes an interesting candidate for the induction of multiple HLA-A *0201-restricted anti-Hsp70 antitumour CTL responses.

The design of a broad application tumor vaccine requires the identification of tumor antigens expressed in a majority of tumors of various origins. We questioned whether the major stress-inducible heat shock protein Hsp70 (also known as Hsp72), a protein frequently overexpressed in human tumors of various histological origins, but not in most physiological normal tissues, constitutes a tumor antigen. We selected the p391 and p393 peptides from the sequence of the human inducible Hsp70 that had a high affinity for HLA-A*0201. These peptides were able to trigger a CTL response in vivo in HLA-A*0201-transgenic HHD mice and in vitro in HLA-A*0201+ healthy donors. p391- and p393-specific human and murine CTL recognized human tumor cells overexpressing Hsp70 in a HLA-A*0201-restricted manner. Tetramer analysis of TILs showed that these Hsp70 epitopes are targets of an immune response in many HLA-A*0201+ breast cancer patients. Hsp70 is a tumor antigen and the Hsp70-derived peptides p391 and p393 could be used to raise a cytotoxic response against tumors of various origins.

EphA2 (Eck) is a tyrosine kinase receptor that is overexpressed in several human cancers such as breast, colon, lung, prostate, gastric carcinoma, and metastatic melanoma but not in nonmalignant counterparts. To validate EphA2 as a tumor antigen recognized by CD8+ T lymphocytes, we used reverse immunology approach to identify HLA-A*0201-restricted epitopes. Peptides bearing the HLA-A*0201-specific anchor motifs were analyzed for their capacity to bind and stabilize the HLA-A*0201 molecules. Two peptides, EphA2(58) and EphA2(550), with a high affinity for HLA-A*0201 were selected. Both peptides were immunogenic in the HLA-A*0201-transgenic HHD mice. Interestingly, peptide-specific murine CTLs cell lines responded to COS-7 cells coexpressing HLA-A*0201 and EphA2 and to EphA2-positive human tumor cells of various origin (renal cell, lung, and colon carcinoma and sarcoma). This demonstrates that EphA2(58) and EphA2(550) are naturally processed from endogenous EphA2. In addition, EphA2(58) and EphA2(550) stimulated specific CD8(+) T cells from healthy donor peripheral blood mononuclear cells. These T cells recognized EphA2-positive human tumor cells in an HLA-A*0201-restricted manner. Interestingly, EphA2-specific CD8+ T cells were detected in the peripheral blood mononuclear cells of prostate cancer patients. These results show for the first time that EphA2 is a tumor rejection antigen and lead us to propose EphA2(58) and EphA2(550) peptides for a broad-spectrum-tumor immunotherapy.

MAGE-A1, -A2, -A3, -A4, -A6, -A10, and -A12 are expressed in a significant proportion of primary and metastatic tumors of various histological types and are targets of tumor Ag-specific CTL. Individual MAGE-A expression varies from one tumor type to the other but, overall, the large majority of tumors expresses at least one MAGE-A Ag. Therefore, targeting epitopes shared by all MAGE-A Ags would be of interest in immunotherapy against a broad spectrum of cancers. In the present study, we describe a heteroclitic MAGE-A peptide (p248V9) that induces CTL in vivo in HLA-A*0201 transgenic HHD mice and in vitro in healthy donors. These CTL are able to recognize two low HLA-A*0201 affinity peptides differing at their C-terminal position and derived from MAGE-A2, -A3, -A4, -A6, -A10, and -A12 (p248G9) and MAGE-A1 (p248D9). Interestingly, p248V9-specific CTL respond to endogenous MAGE-A1, -A2, -A3, -A4, -A6, -A10, and -A12 in an HLA-A*0201-restricted manner and recognize human HLA-A*0201+MAGE-A+ tumor cells of various histological origin. Therefore, this heteroclitic peptide may be considered as a potent candidate for a broad-spectrum tumor vaccination.

Tolerance to tumor-nonmutated self proteins represents a major obstacle for successful cancer immunotherapy. Since this tolerance primarily concerns dominant epitopes, we hypothesized that targeting cryptic epitopes that have a low affinity for HLA could be an efficient strategy to breach the tolerance to tumor Ags. Using the P1Y heteroclitic peptide approach, we identified low affinity cryptic HLA-A*0201-restricted epitopes derived from two widely expressed tumor Ags, HER-2/neu and hTERT. The P1Y variants of four HER-2/neu (neu391, neu402, neu466, neu650)- and two hTERT (hTERT572 and hTERT988)-derived low affinity peptides exhibited strong affinity for HLA-A*0201 and stimulated specific CTL from healthy donor PBMCs. These CTL specifically recognized HER-2/neu- and hTERT-expressing tumor cells of various histological origins. In vivo studies showed that HLA-A*0201 transgenic HHD mice vaccinated with the P1Y variant peptides generated CTL that specifically lysed Ag-expressing tumor cells, thus recognizing the cognate endogenous Ags. These results suggest that heteroclitic variants of low affinity, cryptic epitopes of widely expressed tumor Ags may serve as valid tools for tumor immunotherapy.

In this paper, I start with the opposition between the husserlian project of a phenomenology of the experience of time, started in 1905, and the mathematical and physical theory of time, as it comes out from the special theory of relativity, by Einstein, in the same year. Although the contrast between the two approaches is apparent, my aim is to show that the original program of Husserl’s time theory is the constitution of an objective time and a time of the world, starting from the intuitive giveness of time, i.e., from time as it appears. To show this, I stress the structural similarity between the original question of time, by Husserl, and the problem of a phenomenology of the space constitution, as it was first developed in the husserlian manuscripts of the XIX century, in which we find the threefold question of the origin of our space representation, of the geometrization of intuitive space and the constitution of transcendent world space. Finally, I reconsider some of Husserl’s main theses about the phenomenological constitution of objective time in the light of the main results of special relativity timetheory, introducing several corrections to central assumptions that underlie Husserl’s theory of time.