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One half of a group of 20 patients with human papillomavirus type 16 (HPV16)-induced vulvar intraepithelial neoplasia grade 3 displayed a complete regression (CR) after therapeutic vaccination with HPV16 E6/E7 synthetic long peptides. Patients with relatively larger lesions generally did not display a CR. To investigate immune correlates of treatment failure, patients were grouped according to median lesion size at study entry, and HPV16-specific immunity was analyzed at different time points by complementary immunological assays. The group of patients with smaller lesions displayed stronger and broader vaccine-prompted HPV16-specific proliferative responses with higher IFN[gamma] (P = 0.0003) and IL-5 (P < 0.0001) levels than patients with large lesions. Characteristically, this response was accompanied by a distinct peak in cytokine levels after the first vaccination. In contrast, the patient group with larger lesions mounted higher frequencies of HPV16-specific [CD4.sup.+][CD.sup.25+][Foxp.sup.3+] T cells (P = 0.005) and displayed a lower HPV16-specific IFN[gamma]/IL-10 ratio after vaccination (P < 0.01). No disparity in T memory immunity to control antigens was found, indicating that the differences in HPV-specific immunity did not reflect general immune failure. We observed a strong correlation between a defined set of vaccine-prompted specific immune responses and the clinical efficacy of therapeutic vaccination. Notably, a high ratio of HPV16-specific vaccine-prompted effector T cells to HPV16-specific [CD4.sup.+][CD.sup.25+][Foxp.sup.3+] T cells was predictive of clinical success. [Foxp.sup.3+] T cells have been associated previously with impaired immunity in malignancies. Here we demonstrate that the vaccine-prompted level of this population is associated with early treatment failure. human papilloma virus | immunomonitoring | therapeutic vaccine | regulatory | cells doi/ 10.1073/pnas.1006500107

There is yet no licensed vaccine against malaria, a serious human disease affecting mostly children, with an annual death rate of about one million. Plasmodia, the malaria-causing parasites, have two obligatory hosts: mammals or birds, in which they multiply asexually, and mosquitoes with sexual multiplication. The most common and serious type of malaria is caused by Plasmodium falciparum. The circumsporozoite protein (CSP), a major surface antigen of sporozoites, is a protective antigen. A unique feature of P. falciparum CSP is its large central domain composed of over 30 tetrapeptide repeats of Asn-Ala-Asn-Pro (NANP). Several NANP peptide-protein conjugates were tested clinically but elicited a low level of CSP antibodies for a short duration. To provide a CSP-based candidate vaccine, we investigated recombinant CSP and NANP conjugates of various peptide lengths, with different N-terminal amino acids, bound at different ratios to various carrier proteins. Injected into mice, CSP alone and CSP or NANP conjugates induced antibodies with booster responses and were positive by the sporozoite imunofluorescent assay. The use of the mosquito stage P. falciparum ookinete surface protein, Pfs25, cross-linked onto itself as a carrier for NANP, induced in mice high levels of uniquely long-lasting antibodies to both vaccine components with secondary biological activities, that will provide immunity to liver infection by sporozoites and block transmission by mosquitoes. malaria | circumsporozoite protein | Asn-Ala-Asn-Pro | Plasmodium falciparum ookinete surface protein 25 doi/10.1073/pnas.0913374107

Infliximab, a chimeric monoclonal antibody against TNF-[alpha], is efficacious in Crohn's disease (CD) and rheumatoid arthritis (RA). Its main mechanism of action is thought to be the induction of apoptosis. The present study evaluates in detail the effects of infliximab on the TNF-[alpha] system using peripheral blood monocytes and T cells as well as lamina propria lymphocytes from normal individuals and patients with CD, ulcerative colitis, and RA. Lymphocytes were studied in the resting state in the absence of strong stimuli that may obscure subtle findings. Infliximab did not change the numbers of viable cells. Rather, it caused monocytes to increase their release of soluble TNFR2, which serves to neutralize TNF-[alpha], potentiating the action of infliximab. It reduced TNFR2 expression, thereby decreasing TNF-[alpha] responsiveness. These changes were due to upregulated production of TNFR2 rather than increased shedding. Infliximab did not cause rebound production of TNF-[alpha] transcripts that would counteract its effects. It specifically enhanced production of IL-10 but not proinflammatory cytokines secreted by leukocytes, thereby promoting an anti-inflammatory microenvironment. In addition, infliximab caused a rise in c-Jun amino-terminal kinase phosphorylation by monocytes. Thus infliximab manipulates the TNF-[alpha] system to promote its anti-TNF-[alpha] effects. anti-TNF; lamina propria lymphocytes; macrophages; mucosal immunology

Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is a frequent occurrence in human cancers and a major promoter of chemotherapeutic resistance. Inhibition of one downstream target in this pathway, mTORC1, has shown potential to improve chemosensitivity. However, the mechanisms and genetic modifications that confer sensitivity to mTORC1 inhibitors remain unclear. Here, we demonstrate that loss of TSC2 in the E[micro]-myc murine lymphoma model leads to mTORC1 activation and accelerated oncogenesis caused by a defective apoptotic program despite compromised AKT phosphorylation. Tumors from Tsc[2.sup.+/-]E[micro]-Myc mice underwent rapid apoptosis upon blockade of mTORC1 by rapamycin. We identified myeloid cell leukemia sequence 1 (Mcl-1), a bcl-2 like family member, as a translationally regulated genetic determinant of mTORCl-dependent survival. Our results indicate that the extent by which rapamycin can modulate expression of Mcl-1 is an important feature of the rapamycin response. rapamycin response | Tsc2 loss | apoptosis | lymphoma | Akt

Aluminium adjuvants, typically referred to as 'alum', are the most commonly used adjuvants in human and animal vaccines worldwide, yet the mechanism underlying the stimulation of the immune system by [...]

Immunophilins, protein receptors for immunosuppressant drugs such as cyclosporin A and FK506, are enriched far more in the brain than in the immune system. Drug-immunophilin complexes bind to calcineurin, inhibiting its phosphatase activity and leading to immunosuppressant effects. The immunophilin FKBP-12 (FK506 binding protein, 12 kDa) forms a complex with the ryanodine and inositol (1,4,5) trisphosphate ([IP.sub.3]) receptors to regulate their physiological release of intracellular [Ca.sup.2+]. Here, Solomon Snyder and colleagues describe how non-immunosuppressant as well as immunosuppressant immunophilin ligands are neurotrophic for numerous classes of damaged neurones, both in culture systems and intact animals. Their ability to stimulate functional regrowth of damaged sciatic, cortical cholinergic, dopamine and 5-HT neurones may have therapeutic relevance.

The effects of peptide linker and spacer on the structure and biological activity of fusion proteins used for tumor suppression were examined. Various linkers and spacers were used to join the human gene for human angiogenin (Ang) and a gene for a single-chain antibody (sFv) against human transferrin receptor. The results show that the type of linker affects sFv binding to human transferrin receptor, while a spacer ensures optimal activity of the two halves of the fusion protein. Moreover, the right linker and spacer ensure optimal cytotoxicity of fusion proteins against tumor cells.

Lipid A derived from lipopolysaccharide (LPS) of Porphyromonas gingivalis induces cytokine activities in the macrophage or monocytes of human blood and induces immunopharmacological activities including antiviral, antitumor and natural killer functions. Fatty acids composition and monophosphorylation process of lipid A differs from those of other enterobacterial lipid A proteins. Balanced antagonistic and agonistic effects of lipid A enable its usage as immunomodulatory drug.

Hybridoma technology enabled rodent monoclonal antibodies to be created against human pathogens and cells, but these had limited clinical utility. Protein engineering, reviewed here by Greg Winter and William Harris, is now generating antibodies for treatment of infectious disease, autoimmune disease and cancer by 'humanizing' rodent antibodies. Humanized antibodies have improved pharmacokinetics, reduced immunogenicity and have been used to clinical advantage.

Byline: S. Arokiyaraj, K. Perinbam, P. Agastian, K. Balaraju Four medicinal plant species were collected from the Kolli hills of Tamil Nadu and were screened for their immunosuppressive effect. The [...]