Biomedical subjects

Behazine Combadiere

Publications and source records attributed to Behazine Combadiere.

6 recordsLinked to original sources

PubMed2006

40 nm, but not 750 or 1,500 nm, nanoparticles enter epidermal CD1a+ cells after transcutaneous application on human skin.

Although conventional vaccines have generated major successes in the control of infectious diseases, several obstacles remain in their development against chronic diseases (HIV, tuberculosis), against which no current candidate vaccines yet ensure protection. The transcutaneous route of vaccine administration appears to be a promising approach of targeting vaccines toward antigen-presenting cells (APCs) and thus improving immune responses. We investigated the suitability of nanoparticles in this approach. We found a high density of Langerhans cells (LCs) around hair follicles that, when sorted, readily internalized all size particles. However, flow cytometry after transcutaneous application of 40, 750, or 1,500 nm nanoparticles on human skin samples revealed that only 40 nm particles entered epidermal LC. Fluorescence and laser scan microscopies, which were carried out to identify the penetration pathway of transcutaneously applied nanoparticles, revealed that only 40 nm particles deeply penetrate into vellus hair openings and through the follicular epithelium. We conclude that 40 nm nanoparticles, but not 750 or 1,500 nm nanoparticles, may be efficiently used to transcutaneously deliver vaccine compounds via the hair follicle into cutaneous APCs.

Administration, Cutaneous↗

PubMed2004

Intratumoral CC chemokine ligand 5 overexpression delays tumor growth and increases tumor cell infiltration.

Chemokines participate in the antitumor immune response by regulating the movement and positioning of lymphocytes as well as effector functions and may thus be candidates for use in antitumor therapy. To test whether CCL5, a chemokine involved in the recruitment of a wide spectrum of immunocompetent cells, can control tumor growth, we forced its expression at mouse tumor sites. Tumor growth was reduced in mice with s.c. syngeneic CCL5-EL-4 compared with EL-4-injected mice, whereas both reduced tumor growth and incidence were observed in mice with OVA-expressing EG-7 transfected with CCL5 compared with EG-7-injected mice. Significant antitumor effects were observed soon after intratumoral injection of DNA plasmid coding for chimeric CCL5-Ig. Importantly, quantitative RT-PCR assays showed that the amount of CCL5 expression at the tumor site determined the effectiveness of the antitumor response, which was associated with infiltration of increased numbers of NK, CD4, and CD8 cells at the tumor site. This effect was lost in mice deficient for T/B lymphocytes (RAG-2 knockout) or for CCR5 (CCR5 knockout). Together, these data demonstrate the antitumor activity of intratumoral CCL5 overexpression, due to its recruitment of immunocompetent cells, and the potential usefulness of chimeric CCL5-Ig DNA as an agent in cancer therapy.

Animals↗

PubMed2004

Antigen distribution drives programmed antitumor CD8 cell migration and determines its efficiency.

Understanding both the role of tumor Ag in CD8 cell differentiation and the reasons that CD8 cells may work inefficiently is crucial for therapeutic approaches in cancer. We studied OT-1 CD8 cell responses in vivo in a differential Ag-distribution model that used EG-7, the EL-4 thymoma transfected with OVA. On their initial Ag encounter, OT-1 CD8 cells underwent programmed expansion in the lymph nodes, where they acquired the ability to migrate to the encapsulated tumor site after > or =4 divisions, without continuous antigenic stimulation. This short antigenic stimulation was sufficient to induce the migration differentiation program, which included modulation of chemokine receptor mRNA expression and down-regulation of CD62L. Moreover, Ag quantity determined the behavior of the OT-1 CD8 cells, including their effector functions and sensitivity to apoptosis. Thus, the initial Ag encounter drives the programmed cell migration potencies, but neither effector functions nor cell death can occur without continuous TCR triggering.

Animals↗

PubMed2004

Distinct time effects of vaccination on long-term proliferative and IFN-gamma-producing T cell memory to smallpox in humans.

Residual immunity to the smallpox virus raises key questions about the persistence of long-term immune memory in the absence of antigen, since vaccination ended in 1980. IFN-gamma-producing effector-memory and proliferative memory T cells were compared in 79 vaccinees 13-25 yr after their last immunization and in unvaccinated individuals. Only 20% of the vaccinees displayed both immediate IFN-gamma-producing effector-memory responses and proliferative memory responses at 6 d; 52.5% showed only proliferative responses; and 27.5% had no detectable vaccinia-specific responses at all. Both responses were mediated by CD4 and CD8 T cells. The vaccinia-specific IFN-gamma-producing cells were composed mainly of CD4Pos CD45RANeg CD11aHi CD27Pos and CCR7Neg T cells. Their frequency was low but could be expanded in vitro within 7 d. Time since first immunization affected their persistence: they vanished 45 yr after priming, but proliferative responses remained detectable. The number of recalls did not affect the persistence of residual effector-memory T cells. Programmed revaccination boosted both IFN-gamma and proliferative responses within 2 mo of recall, even in vaccinees with previously undetectable residual effector-memory cells. Such long-term maintenance of vaccinia-specific immune memory in the absence of smallpox virus modifies our understanding of the mechanism of persistence of long-term memory to poxviruses and challenges vaccination strategies.

Adult↗

PubMed2004

Interplay between cell division and cell death during TCR triggering.

Cell death is crucial to avoid excessive T cell expansion. During primary T cell expansion in response to pathogen or after vaccination, the amount of foreign Ag determines the degree of clonal amplification and death. Here, we studied the balance between cell proliferation and death, as well as susceptibility to cell death, during TCR triggering. After priming of CD4 T cells from AND-TCR (Vbeta3, Valpha11)-transgenic mice with a high dose of pigeon cytochrome c peptide 88-104, the cell expansion rate was significantly reduced by marked clonal elimination compared to lower Ag doses, whereas the number of cell divisions reached was similar at all Ag doses. TCR re-engagement on activated T cells induced cell death, irrespective of the dose of Ag encountered during primary stimulation. Surprisingly, commitment to apoptosis occurred as early as the first division on all dividing cells both in vitro and in vivo. This phenomenon was highly selective, as activated but non-dividing cells did not undergo cell death, whereas cells that had divided once became susceptible to cell death. These findings have direct implications for the peripheral homeostatic mechanism following Ag challenge and for designing primary/booster vaccine strategies.

Animals↗

PubMed2003

Perforin-dependent brain-infiltrating cytotoxic CD8+ T lymphocytes mediate experimental cerebral malaria pathogenesis.

Experimental cerebral malaria (ECM) resulting from Plasmodium berghei ANKA infection involves T lymphocytes. However, the mechanisms of T cell-mediated pathogenesis remain unknown. We found that, in contrast to ECM-susceptible C57BL6 mice, perforin-deficient (PFP-KO) mice were resistant to ECM in the absence of brain lesions, whereas cytoadherence of parasitized erythrocytes and massive accumulation of activated/effector CD8 lymphocytes were observed in both groups of mice. ECM is induced in PFP-KO mice after adoptive transfer of cytotoxic CD8+ cells from infected C57BL6 mice, which were directed to the brain of PFP-KO mice. This specific recruitment might involve chemokine/chemokine receptors, since their expression was up-regulated on activated CD8 cells, and susceptibility to ECM was delayed in CCR5-KO mice. Thus, lymphocyte cytotoxicity and cell trafficking are key players in ECM pathogenesis.

Adoptive Transfer↗