Re: Re: dendritic cells: promising method of inducing peripheral tolerance?

Annonymous,

Thank you for your timely question. Dendritic Cells are now very much in everyone's interest. Hardly anyone knew about dendritic cells only 25 years ago but the work of Ralph Steinman at the Rockefeller University in New York and Gordon McPherson at Oxford had at that time already begun to show how important these cells are in triggering immune responses by presenting antigens. Steiman's work showed that these cells were hundreds of times more potent as antigen presenting cells than were macrophages or other cells.

So, now we are becoming interested in tolerance induction by dendritic cells. Antigen Specific Tolerance being the opposite intention than the original observations of Antigen Presentation for initiation of immune responses.

In 1979 I personally had stumbled upon dendritic cells in an assay I was studying that involved using lymphoid appearing cells in efferent lymph.
Transpla nt Proc. 1981 Jun;13(2):1460-8.
"Presence of lymphoid dendritic cells in thoracic duct lymph from Lewis rats".
Anderson AO, Warren JT, Gasser DL.

Actually, the cells in thoracic duct lymph were supposed to be 100% lymphocytes since efferent lymph at that time was thought to be completely devoid of antigen presenting cells. Time proved that lymph is a medium for transport of antigen presenting cells from places of antigen uptake to places where antigen is presented.

In Thoracic duct lymph, I found two forms of dendritic cells that differed according to whether they expressed complement (C3b) receptors. Those that lacked C3b receptors primed effectively for cytotoxic T-cell activation but suppressed antibody production in mixed lymphocyte assays while those that had C3b receptors seemed to suppress cytotoxic T-cell activation and supported antibody production in mixed lymphocyte assays. Others also found that at least two kinds of dendritic cells were present and this had bearing on what kind of immune response, or whether an immune response, would be initiated. These differences might equate to some investigators as tolerance induction if they found no response of the type they were looking for but failed to look for the kind of response that was initiated.

Here are some more current online finds related specifically to your question about means of inducing tolerance with dendritic cells.

http://www.pubmedcentral.nih.gov/articlere nder.fcgi?artid=27123&rendertype=abstract
Mature immunologically competent dendritic cells are the most efficient antigen-presenting cells that powerfully activate T cells and initiate and sustain immune responses. Indeed, dendritic cells are able to efficiently capture antigens, express high levels of costimulatory molecules, and produce the combination of cytokines required to create a powerful immune response. They are also considered to be important in initiating autoimmune disease by efficiently presenting autoantigens to self-reactive T cells that, in this case, will mount a pathogenic autoimmune reaction. Triggering T cells is not a simple on–off procedure, as T cell receptor responds to minor changes in ligand with gradations of T cell activation and effector functions. These “misfit” peptides have been called Altered Peptide Ligands, and have been shown to have important biological significance. Here, we show that fully capable dendritic cells may present, upon natural antigen processing, a self-epitope with Altered Peptide Ligands features that can unexpectedly induce anergy in a human autoreactive T cell clone. These results indicate that presentation of a self-epitope by immunologically competent dendritic cells does not always mean “danger” and show a mechanism involved in the fine balance between activation and tolerance induction in humans.

http://www.pubmedcentral.nih.gov/pi crender.fcgi?artid=27123&action=stream&blobtype=pdf

http://www.pubmedcentral.nih.gov/articler ender.fcgi?artid=449750&rendertype=abstract

One mechanism contributing to immunologic unresponsiveness toward tumors may be presentation of tumor antigens by tolerogenic host APCs. We show that mouse tumor-draining LNs (TDLNs) contained a subset of plasmacytoid DCs (pDCs) that constitutively expressed immunosuppressive levels of the enzyme indoleamine 2,3-dioxygenase (IDO). Despite comprising only 0.5% of LN cells, these pDCs in vitro potently suppressed T cell responses to antigens presented by the pDCs themselves and also, in a dominant fashion, suppressed T cell responses to third-party antigens presented by nonsuppressive APCs. Adoptive transfer of DCs from TDLNs into naive hosts created profound local T cell anergy, specifically toward antigens expressed by the transferred DCs. Anergy was prevented by targeted disruption of the IDO gene in the DCs or by administration of the IDO inhibitor drug 1-methyl-D-tryptophan to recipient mice. Within the population of pDCs, the majority of the functional IDO-mediated suppressor activity segregated with a novel subset of pDCs coexpressing the B-lineage marker CD19. We hypothesize that IDO-mediated suppression by pDCs in TDLNs creates a local microenvironment that is potently suppressive of host antitumor T cell responses.

http://www.pubmedcentral.nih.gov/p icrender.fcgi?artid=449750&action=stream&blobtype=pdf

http://www.obgyn.net/newsheadlines/headline_medical_news- Niigata_University-20040505-6.asp

IL-10-treated dendritic cells may induce GVHD risk

Niigata University
May 5, 2004


Dendritic cells treated with interleukin (IL)-10 may help prevent graft- versus-host reactions in stem-cell transplant recipients.

"In order to apply for reducing graft versus host disease in allogeneic stem cell transplantation," a study "concerning the induction of specific T-cell anergy" was conducted by researchers in Japan.

"Normal allogeneic lymphocytes, which were co-cultured with IL-10-treated immature dendritic cells in the first mixed leukocyte culture (MLC), were cultured with mature dendritic cells of the same origin as IL-10-treated immature dendritic cells in the second MLC," explained Z.Y. Zheng and coauthors at Niigata University.

"By co-culturing with IL-10-treated immature dendritic cells, the response of normal lymphocytes to mature dendritic cells cultured from the same individual as that of IL-10-treated dendritic cells was markedly reduced, compared with the lymphocytes cultured with nontreated dendritic cells or IL-10-treated dendritic cells from a third party individual," test results revealed.

"The present study demonstrated that antigen specific T-cell anergy was generated by priming allogeneic lymphocytes with IL-10-treated immature dendritic cells," the investigators concluded. "These data suggested the applicability of IL-10-treated recipient dendritic cells for the induction of recipient cell-specific donor T-cell anergy in donor graft."

Zheng and colleagues published their study in Comparative Immunology Microbiology and Infectious Diseases (Induction of T cell anergy by the treatment with IL-10-treated dendritic cells. Comp Immunol Microbiol Infect, 2004;27(2):93-103).

For additional information, contact M. Takahashi, Niigata University, Faculty of Medicine, School of Health Sciences, 2-746 Asahimachi, Niigata, Japan.

Publisher contact information for the journal Comparative Immunology Microbiology and Infectious Diseases is: Pergamon-Elsevier Science Ltd., the Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, England. http://www.in genta.com/isis/searching/ExpandTOC/ingenta? issue=infobike://els/01479571/2004/00000027/00000002&index=4

Induction of T cell anergy by the treatment with IL-10-treated dendritic cells

Comparative Immunology, Microbiology and Infectious Diseases
March 2004, vol. 27, no. 2, pp. 93-103(11)
Zheng Z.; Narita M.; Takahashi M.[1]; Liu A.; Furukawa T.; Toba K.; Aizawa Y.
[1]School of Health Sciences, Faculty of Medicine, Niigata University, 2- 746, Asahimachi, , Niigata, Japan

Keywords: T cell anergy; IL-10; Dendritic cells; Allogeneic stem cell transplantation; Expansion of donor candidates; Anergie des cellules T; IL- 10; Cellules dendritiques; Transplantation de cellules souches allogeniques; Multiplication des donneurs potentiels
Language: English Document Type: Research article ISSN: 0147-9571 DOI (article): 10.1016/S0147-9571(03)00054-7 SICI (online): 0147-957127293103

Inhibition of Myeloid Dendritic Cell Accessory Cell Function and Induction of T Cell Anergy by Alcohol Correlates with Decreased IL-12 Production1,2

Pranoti Mandrekar, Donna Catalano, Angela Dolganiuc, Karen Kodys and Gyongyi Szabo3
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605

Alcohol consumption inhibits accessory cell function and Ag-specific T cell responses. Myeloid dendritic cells (DCs) coordinate innate immune responses and T cell activation. In this report, we found that in vivo moderate alcohol intake (0.8 g/kg of body weight) in normal volunteers inhibited DC allostimulatory capacity. Furthermore, in vitro alcohol treatment during DC differentiation significantly reduced allostimulatory activity in a MLR using naive CD4+ T cells, and inhibited tetanus toxoid Ag presentation by DCs. Alcohol-treated DCs showed reduced IL-12, increased IL-10 production, and a decrease in expression of the costimulatory molecules CD80 and CD86. Addition of exogenous IL-12 and IL- 2, but not neutralization of IL-10, during MLR ameliorated the reduced allostimulatory capacity of alcohol-treated DCs. Naive CD4+ T cells primed with alcohol-treated DCs showed decreased IFN- production that was restored by exogenous IL-12, indicating inhibition of Th1 responses. Furthermore, CD4+ T cells primed with alcohol-treated DCs were hyporesponsive to subsequent stimulation with the same donor-derived normal DCs, suggesting the ability of alcohol-treated DCs to induce T cell anergy. LPS-induced maturation of alcohol-treated immature DCs partially restored the reduced allostimulatory activity, whereas alcohol given only during DC maturation failed to inhibit DC functions, suggesting that alcohol primarily impairs DC differentiation rather than maturation. NF B activation, a marker of DC maturation was not affected by alcohol. Taken together, alcohol both in vitro and in vivo can impair generation of Th1 immune responses via inhibition of DC differentiation and accessory cell function through mechanisms that involve decreased IL-12 induction.

A tumor-associated and self antigen peptide presented by dendritic cells may induce T cell anergy in vivo, but IL-12 can prevent or revert the anergic state

U Grohmann, R Bianchi, E Ayroldi, ML Belladonna, D Surace, MC Fioretti and P Puccetti
Department of Experimental Medicine, University of Perugia, Italy.

Ag-specific CD8+ cell responses, including delayed-type hypersensitivity in vivo and IFN-gamma production in vitro, are initiated by host immunization with P815AB, a self peptide bearing CTL epitopes and expressed by murine mastocytoma cells. Using P815AB-pulsed dendritic cells (DC) and monitoring class I-restricted skin test reactivity in DC-primed mice, we have previously shown that the development of a Th1-like response to P815AB requires T helper effects, such as those mediated by coimmunization with class II-restricted (helper) peptides or by the use of rIL-12. The adjuvanticity of IL-12 was suggested to involve improved recognition of class II-restricted epitopes of P815AB. In the present study, we provide evidence for the occurrence of I-A(d)-restricted epitopes in the tumor peptide. We also show that in the absence of helper peptide or rIL-12, P81 5AB not only failed to initiate CD8+ cell responses in vivo and in vitro, but resulted in a transient state of functional unresponsiveness, characterized by a profound inability of CD4+ cells to produce IL-2 in vitro. Ag-specific T cell anergy was also observed after neutralization of endogenous IL-12 at the time of priming with P815AB plus helper peptide. All of these effects were reversed by rIL-12, which was added to DC cultures and administered to the DC-recipient mice. Anergy induction may thus contribute to P81 5AB unresponsiveness in vivo. IL- 12 may act to prevent or revert anergy to this tumor-associated and self peptide.