Dendritic Cells, Therapeutic Vectors of Immunity and Tolerance (2005)

Pharmacological immunosuppression is essential for allograft and patient survival, but drug dosage must be carefully balanced in order to prevent episodes of acute rejection, without compromising host defenses against life threatening infections or cancers. Severe immunodeficiency, resulting from the obliteration of the immune system by indiscriminative drug treatments could be avoided with novel therapeutic strategies exploiting mechanisms involved in the induction of antigen-specific immunologic tolerance. In this issue of the American Journal of TransplantationTaner et al. present a dendritic cell-based therapy for inducing graft tolerance, without the need for deleterious pharmacological treatments (1Taner T Hackstein H Wang Z Morelli AE Thomson AW Rapamycin-treated, alloantigen-pulsed host dendritic cells induce Ag-specific T cell regulation and prolong graft survival..Am J Transplant. 2005; 5: 228-236Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar).The authors show in a mouse model that the administration of autologous DCs treated with rapamycin and pulsed with donor antigens significantly prolongs heart allograft survival. Dendritic cells (DC) play a crucial role in the establishment of both central and peripheral tolerance see(2Steinman RM Hawiger D Nussenzweig MC Tolerogenic dendritic cells..Annu Rev Immunol. 2003; 21: 685Crossref PubMed Scopus (2632) Google Scholar) for review). In the periphery, transfer of tissue antigens to DCs at the steady state results in the neutralization of reactive T cells that escaped deletion in the thymus and establishment of systemic antigen-specific tolerance. Tissue resident DCs uptake apoptotic bodies resulting from homeostatic turnover, and migrate to secondary lymphoid organs to present tissue-derived antigens. These migratory DCs acquire morphological and phenotypical features characteristic of partially mature DCs and possess tolerogenic properties (3Lutz MB Schuler G Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity?.Trends Immunol. 2002; 23: 445Abstract Full Text Full Text PDF PubMed Scopus (1172) Google Scholar). Antigens acquired by DCs via uptake of cellular debris or capture of soluble proteins are processed for presentation on both MHC class I and class II. In the periphery DCs mediate tolerance through the neutralization of reactive T cells (deletion, anergy, or inactivation) and the development of naturally occurring CD4+ CD25+ suppressor T cells produced in the thymus,and/or induced regulatory T cells (TR)derived from peripheral CD4+CD25- T cells. Interestingly, the immunoregu- latory function of DCs is not limited to the conversion of naïve or effector T cells to an anergic or suppressor phenotype. A recent report indicates that DCs are capable of expanding populations of CD4+CD25+ suppressor T cells in an antigen-specific manner (4Yamazaki S lyoda T Tarbell K et al.Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells..J Exp Med. 2003; 198: 235Crossref PubMed Scopus (769) Google Scholar). Tolerogenic DCs are perceived as a promising means of improving transplantation outcomes through both direct (donor DCs) or indirect (transfer of donor antigens to recipient DCs)allorecognition pathways. The challenge is to identify the DCs which are best suited to promote therapeutic tolerance: (i) Immature DCs possess inherent tolerogenic properties, and repetitive injections of immature DCs was found to prolong cardiac allograft survival (5Fu F Li Y Qian S et al.Costimulatory molecule-deficient dendritic cell progenitors (MHC class II+, CD80dim, CD86-) prolong cardiac allograft survival in nonimmunosuppressed recipients..Transplantation. 1996; 62: 659Crossref PubMed Scopus (354) Google Scholar).DCs appear however capable of maturing in vivo upon injection, prompting the development of strategies aiming at stabilizing DCs phenotype (ii) Tolerogenic DCs can be obtained through immunological conditioning. Indeed, murine bone marrow DCs cultivated in the presence of TNF-alpha acquire tolerogenic properties (6Menges M Rossner S Voigtlander C et al.Repetitive injections of dendritic cells matured with tumor necrosis factor alpha induce antigen-specific protection of mice from autoimmunity..J Exp Med. 2002; 195: 15Crossref PubMed Scopus (523) Google Scholar). DCs with similar characteristics can be derived in the presence of IL-10 prior to exposure to inflammatory microbial stimuli, and were found to induce CD4+ and CD8+ anergic T-cells (7Sato K Yamashita N Matsuyama T Human peripheral blood monocyte-derived interleukin-10-induced semi-mature dendritic cells induce anergic CD4(+) and CD8(+) T cells via presentation of the internalized soluble antigen and cross-presentation of the phagocytosed necrotic cellular fragments..Cell Immunol. 2002; 215: 186Crossref PubMed Scopus (61) Google Scholar).Furthermore, engagement of DC cell surface receptors by T- cell derived inhibitory molecule CTLA4 elicits IDO expression and promotes tolerogenicity (8Mellor AL Munn DH Ido expression by dendritic cells: tolerance and tryptophan catabolism..Nat Rev Immunol. 2004; 4: 762Crossref PubMed Scopus (1872) Google Scholar).(iii) Tolerogenic DCs can be obtained through pharmacological conditioning (9Hackstein H Thomson AW Dendritic cells: emerging pharmacological targets of immunosuppressive drugs..Nat Rev Immunol. 2004; 4: 24Crossref PubMed Scopus (490) Google Scholar).Pharmacologic agents interfering with the NF-kB signaling pathway are used to generate tolerogenic DCs.Ra- pamycin which was used in the present study, inhibits DC maturation, inflammatory cytokine production (IL-12, TNF-α), and promotes T-cell anergy. Vitamin D3 analogs decrease the expression of co-stimulatory molecules, elicit low IL-12 and enhanced IL-10 secretion and elicit CD4+ CD25+ T suppressor cells. Other well known immunosuppressive drugs affect DC function: calcineurin inhibitors (cyclosporine, tacrolimus) block the activity of transcription factor belonging to the Nuclear Factor of Activated T cell (NFAT) family, and the immunophilin-binding immunosuppressant Sanglifehrin A blocks IL-12 and TNF-α production. While exposure to donor antigens at the steady state is unlikely to elicit adverse immune reactions, the trauma of surgery and ischemia-reperfusion inevitably creates a pro-inflammatory environment that instigates immunogenic presentation of donor-derived antigens by mature DCs. Therapeutic tolerance induction must therefore be achieved by delivering donor antigens at the steady state. To prevent the risk of inadvertent maturation in vivo, which would have the opposite effect to that intended, Thomson et al. treated DCs in vitro with rapamycin (1Taner T Hackstein H Wang Z Morelli AE Thomson AW Rapamycin-treated, alloantigen-pulsed host dendritic cells induce Ag-specific T cell regulation and prolong graft survival..Am J Transplant. 2005; 5: 228-236Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar).The authors show that multiple injections of pharmacologically conditioned DC preparations lead to long term heart allograft survival. Prolonged graft survival conferred by DC treatment was further extended by a short course of FK506. This finding indicates that inflammation resulting from transplant surgery interferes with DC treatment, a fact confirmed by the loss of graft protection observed upon administration of exogenous interleukin-2.Because rapamycin-conditioned DCsappear to promote reversible allospecific T cell hyporesponsiveness, one can wonder if the generation of suppressor T cell populations, which have recently been associated with operational allograft tolerance state in liver transplant patients (10Li Y Yoshizawa A et al.Analyses of peripheral blood mononuclear cells in operational tolerance after pediatric living donor liver transplantation..Am J Transplant. 2004; 4: 2118-2125Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar),could lead to enhanced graft protection. Also, studies following up on this seminal work need to investigate whether it is possible to impact a wider range of T-cell tolerance mechanisms. In contrast with prior studies this work utilize autologous DCs pulsed with donor derived antigens as a means to induce allograft tolerance, a strategy that is comparable to the one used in DC-based cancer vaccine therapy, suggesting that depending on their activation status DCs preparations could produce therapeutic effects mediated by opposite arms of the immune response. Because it exploits strategies that have been applied in clinical settings for several years for the treatment of cancer, this work will facilitate the promotion of DC-based transplant tolerance induction regimens. Several critical parameters—including DC cultures, conditioning and antigen loading, as well as timing, site and frequency of injection—need to be evaluated carefully through extensive studies in human subjects in order to establish safe and reliable DC-based tolerance induction therapy. Alternative approaches will also have to be explored. Most notably DCs express adsorptive mono- and multi-lectin endocytic receptors that can be used to target antigens for processing and presentation by DCs in vivo. Hence, it has been shown that in the absence of stimulation, addressing peptides or proteins through the multi-lectin receptor DEC-205 promotes antigen-specific tolerance (11Bonifaz L Bonnyay D Mahnke K Rivera M Nussenzweig MC Steinman RM Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ Tcell tolerance..J Exp Med. 2002; 196: 1627Crossref PubMed Scopus (1097) Google Scholar). However because the strategy used in the present work permits the presentation of complex antigenic mixtures it is likely to pave the way for the future use of DCs as therapeutic vectors of tolerance.