Clinical and applied immunology reviews最新文献

P-glycoproteins (P-gp) are widely known for their ability to pump drugs out of multidrug-resistant tumor cells, but are also normally expressed in a variety of nonmalignant tissues in mammals. In particular, lymphocytes and other hematopoietic cell lineages express P-gps during development and upon maturation in the periphery. However, the physiological significance of their expression in lymphocytes has been difficult to establish directly, although putative roles in cytotoxic function and cytokine release have previously been suggested. Progress toward resolving the actual nature of P-gp action in vivo has lately been aided by the production of P-gp-deficient mouse lines. Recent studies using these animals and data presented here indicate that P-gps are not required by peripheral T-lymphocytes for development or effector functions, but suggest they may have a role in the establishment or maintenance of certain T-cell population balances in the gut.

P-glycoprotein (P-gp), a member of the adenosine triphosphate (ATP)-binding cassette (ABC) family of transporter molecules, is responsible for maintaining low intracellular concentrations of a variety of extracellular compounds and xenobiotics, and for transport of various intracellular molecules. Many drugs are P-gp substrates and intracellular concentrations of these agents may be critical for drug action. Experience in oncology indicates that repeated exposure to P-gp substrate cytotoxic drugs leads to the selection of drug-resistant tumor cells that overexpress P-gp. Since immunosuppressive agents such as cyclosporine, tacrolimus, sirolimus and corticosteroids are substrates for P-gp and since T-cells also express P-gp, it is conceivable that an analogous mechanism exits for therapy-resistant graft rejection. As will be discussed in this article, P-gp may interfere with the response to immunosuppressive therapy through several distinct mechanisms, and as such may represent an attractive therapeutic target.

Multidrug resistance (MDR) mediated by the adenosine triphosphate (ATP)-dependent drug efflux protein P-glycoprotein (P-gp), is a major obstacle to the successful treatment of cancer. P-gp is expressed in many types of cancers and the clinical success of chemotherapeutic treatment often correlates inversely with the level of P-gp expression. P-gp is a 170–180 kD cell-surface transporter protein and has historically been thought to confer resistance to chemotoxins by actively effluxing them from the cell. While there is little doubt that P-gp plays an important role as an efflux pump in conferring multidrug resistance, new evidence is mounting to suggest that in addition, P-gp may act as a general anti-apoptotic protein to increase the threshold for cell death. Effectively, P-gp may protect cells at two levels, firstly by decreasing the amount of toxins that accumulate in the cell, and secondly by blocking apoptotic pathways induced by toxins and cellular stress. Understanding how P-gp can regulate cell death could lead to novel therapies for the treatment of MDR tumors.

P-glycoprotein (P-gp), the human multidrug resistant (MDR1) gene product and cancer multidrug resistance-associated adenosine triphosphate (ATP)-binding cassette (ABC) transporter, is physiologically expressed on peripheral blood mononuclear cells, but its role in cellular immunity is only beginning to be elucidated. A role of P-gp in the secretion of several T-cell and antigen presenting cell-derived cytokines has been described, and additional functions of the molecule have been identified in lymphocyte survival and antigen presenting cell differentiation. Taken together, these findings provide compelling evidence that P-gp serves several distinct functions in the initiation of primary immune responses, and a critical role of the molecule in functional alloimmune responses is now established. Here, we will review the current understanding of P-gp function in alloimmune T-cell activation via both T-cell and antigen presenting cell-dependent mechanisms, which is relevant to the field of clinical transplantation, where P-gp has been found to be a marker of acute and chronic allograft rejection. Indeed, current in vitro findings raise the possibility that P-gp could represent a novel therapeutic target in acute and chronic allograft rejection, the major causes of allograft dysfunction and ultimate graft loss.

Transforming growth factor beta (TGF-β) is a multifunctional cytokine, whose myriad of functions include its ability to potently suppress the immune system. Because of its ability to negatively modulate the inductive and effector phases of the immune response, TGF-β is thought to contribute to tumor progression and metastases formation. Immunosuppression by tumor-derived TGF-β is increasingly becoming recognized as an important factor in tumor progression and may, in part, explain the low response rates achieved in cancer patients undergoing immunotherapy for their disease. This review will focus on the immunosuppressive role of tumor-derived TGF-β in breast cancer. Due to the paucity of human studies, it will specifically address the actions of tumor-derived TGF-β on cells of the immune system in preclinical animal models, as well as discuss strategies to negate the deleterious effects of TGF-β in order to improve the anti-tumor immune response.

The introduction of potent antiretroviral therapy (ART) has generated hope and prospects in the management of human immunodeficiency virus-1 (HIV-1) infection. Long-term side effects of ART, however, have also indicated the limitations of this approach alone. A decade ago, immune therapy trials in HIV-1-infected individuals were performed in the absence of ART with a gp160-based vaccine [1]. At that time, the notion that the HIV-1 env obtained from lab-adapted strains would be a poor inducer of antibodies able to neutralize primary HIV-1 isolates was in its infancy [2]. Similarly, the importance of cell-mediated immune response in the containment of HIV-1 replication both in acute and chronic infection 3, 4, 5, 6, 7, 8, albeit predictable from other models of viral infection, was not fully appreciated. Here, attempts to model immune intervention in SIVmac251-infected macaques using vaccines able to elicit cell-mediated immune responses will be reviewed.

The introduction of ART has resulted in effective suppression of viral replication and decreased morbidity and mortality of HIV-1-infected individuals [9]. The decreased morbidity appears to be associated with the reconstitution of immune responses to pathogens, such as cytomegalovirus and Epstein-Barr virus 10, 11, 12. However, HIV-1-specific immune responses decline during ART treatment of adults and children 13, 14, 15, 16, 17, perhaps because of a decrease of HIV-1 replication and antigen exposure under ART. The wide use of ART has also resulted in a better appreciation of the limitations of this daily multi-drug combination treatment, such as compliance 18, 19, due to the complexity of treatment and life-threatening side effects after long-term treatment 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30.