Induction Of Immunological Tolerance Research Articles

Membrane and Soluble ILT3 Are Critical to the Generation of T Suppressor Cells and Induction of Immunological Tolerance

The tolerogenic phenotype of human dendritic cells is characterized by high cell surface expression of the inhibitory receptor ILT3. ILT3 signals both intracellularly inhibiting tyrosine phosphorylation, NF-κB and MAPK p38 activity, transcription of certain co-stimulatory molecules, secretion of cytokines and chemokines, and extracellularly into the T cells with which the dendritic cells interact. Both ILT3 high tolerogenic dendritic cells and soluble ILT3 induce CD4 Th anergy and differentiation of antigen specific CD8 T suppressor cells. Recombinant ILT3-Fc protein has important immunotherapeutic potential acting directly on activated T cells and promoting the induction of immunological tolerance.

Long term immunologic consequences of experimental stroke and mucosal tolerance

BackgroundAn inflammatory insult following middle cerebral artery occlusion (MCAO) is associated with a predisposition to develop a deleterious autoimmune response to the brain antigen myelin basic protein (MBP). Induction of immunologic tolerance to brain antigens prior to MCAO prevents this deleterious autoimmune response and is associated with better functional outcome early after stroke. In this study, we sought to determine the long term immunologic consequences of experimental stroke and induction of mucosal tolerance.MethodsMale Lewis rats were tolerized to MBP or ovalbumin (OVA) by intranasal administration prior to MCAO and administration of lipopolysaccharide (LPS). Neurological outcome was assessed at set points after MCAO and animals sacrificed at 3 months; the immune response to MBP in brain and spleen was determined using ELISPOT assay and degree of cellular inflammatory brain infiltrate assessed by immunocytochemistry.ResultsAnimals that developed a pro-inflammatory (TH1) response to MBP experienced worse outcome, while those that developed a regulatory response (TREG) experienced better outcome. A TREG response in spleen was also associated with decreased inflammation and an increase in the number of FoxP3 positive cells in brain. In this study, tolerization to MBP prior to MCAO was associated with a tendency to develop a TH1 response to MBP by 3 months after MCAO.ConclusionThese data show that induction of immunological tolerance to MBP is associated with improved outcome after stroke. This study, however, raises concern about the potential for inadvertent induction of detrimental autoimmunity through mucosal administration of antigen.

Mucosally induced Immunological Tolerance, Regulatory T Cells and the Adjuvant Effect by Cholera Toxin B Subunit

Induction of peripheral immunological tolerance by mucosal administration of selected antigens (Ags) ('oral tolerance') is an attractive, yet medically little developed, approach to prevent or treat selected autoimmune or allergic disorders. A highly effective way to maximize oral tolerance induction for immunotherapeutic purposes is to administer the relevant Ag together with, and preferably linked to the non-toxic B subunit protein of cholera toxin (CTB). Oral, nasal or sublingual administration of such Ag/CTB conjugates or gene fusion proteins have been found to induce tolerance with superior efficiency compared with administration of Ag alone, including the suppression of various autoimmune disorders and allergies in animal models. In a proof-of-concept clinical trial in patients with Behcet's disease, this was extended with highly promising results to prevent relapse of autoimmune uveitis. Tolerization by mucosal Ag/CTB administration results in a strong increase in Ag-specific regulatory CD4(+) T cells, apparently via two separate pathways: one using B cells as APCs and leading to a strong expansion of Foxp3(+) Treg cells which can both suppress and mediate apoptotic depletion of effector T cells, and one being B cell-independent and associated with development of Foxp3(-) regulatory T cells that express membrane latency-associated peptide and transforming growth factor (TGF-beta) and/or IL-10. The ability of CTB to dramatically increase mucosal Ag uptake and presentation by different APCs through binding to GM1 ganglioside (which makes most B cells effective APCs irrespective of their Ag specificity), together with CTB-mediated stimulation of TGF-beta and IL-10 production and inhibition of IL-6 formation may explain the dramatic potentiation of oral tolerance by mucosal Ags presented with CTB.

Noninvasive methods to assess the risk of kidney transplant rejection

In current clinical practice, immune reactivity of kidney transplant recipients is estimated by monitoring the levels of immunosuppressive drugs, and by functional and/or histological evaluation of the allograft. The availability of assays that could directly quantify the extent of the recipient’s immune response towards the allograft would help clinicians to customize the prescription of immunosuppressive drugs to individual patients. Importantly, these assays might provide a more in-depth understanding of the complex mechanisms of acute rejection, chronic injury, and tolerance in organ transplantation, allowing the design of new and potentially more effective strategies for the minimization of immunosuppression, or even for the induction of immunological tolerance. The purpose of this review is to summarize results from recent studies in this field.

A murine model for induction of long-term immunologic tolerance to factor VIII does not require persistent detectable levels of plasma factor VIII and involves contributions from Foxp3+ T regulatory cells

AbstractUnder certain instances, factor VIII (FVIII) stimulates an immune response, and the resulting neutralizing antibodies present a significant clinical challenge. Immunotherapies to re-establish or induce long-term tolerance would be beneficial, and an in-depth knowledge of mechanisms involved in tolerance induction is essential to develop immune-modulating strategies. We have developed a murine model system for studying mechanisms involved in induction of immunologic tolerance to FVIII in hemophilia A mice. We used lentiviral vectors to deliver the canine FVIII transgene to neonatal hemophilic mice and demonstrated that induction of long-term FVIII tolerance could be achieved. Hemophilia A mice are capable of mounting a robust immune response to FVIII after neonatal gene transfer, and tolerance induction is dependent on the route of delivery and type of promoter used. High-level expression of FVIII was not required for tolerance induction and, indeed, tolerance developed in some animals without evidence of detectable plasma FVIII. Tolerance to FVIII could be adoptively transferred to naive hemophilia recipient mice, and FVIII-stimulated splenocytes isolated from tolerized mice expressed increased levels of interleukin-10 and decreased levels of interleukin-6 and interferon-γ. Finally, induction of FVIII tolerance mediated by this protocol is associated with a FVIII-expandable population of CD4+CD25+Foxp3+ regulatory T cells.

The molecular mechanisms of immunomodulation and tolerance induction to factor VIII.

Successful factor (F) VIII replacement therapy in hemophilia A patients is confounded by the generation of inhibitory anti-FVIII antibodies (Ab) in 25-30% of treated patients. These antibodies, termed 'inhibitors', significantly increase morbidity within the hemophilia population and lower the quality of life for these patients. For the past 30 years, immune tolerance induction (ITI) has been the standard therapy to elicit immunological tolerance to FVIII in the clinic. ITI works well in approximately 75% of patients, but it is expensive, can take years to show effect and is in many cases practically challenging. Therefore, new immunological tolerance induction strategies are now being designed and tested in hemophilia A animal models. This review attempts to provide a comprehensive description, at both the cellular and molecular levels, of these novel advances in tolerance induction and immunomodulation of FVIII. We begin by briefly reviewing why and how the immune system generates a protective response against exogenous FVIII. This leads to a discussion of the latest advances in FVIII tolerance/immunomodulation technology. These advances include interesting methodologies to induce B cell specific tolerance in FVIII primed humans and animals, as well as newer T cell-specific therapies that modify and/or block co-stimulation. We also discuss methods to manipulate FVIII loading of antigen-presenting cells.

Regulation of Rat and Human T-Cell Immune Response by Pharmacologically Modified Dendritic Cells

The central function of dendritic cells (DC) in inducing and preventing immune responses makes them ideal therapeutic targets for the induction of immunologic tolerance. In a rat in vivo model, we showed that dexamethasone-treated DC (Dex-DC) induced indirect pathway-mediated regulation and that CD4+CD25+ T cells were involved in the observed effects. The aim of the present study was to investigate the mechanisms underlying the acquired immunoregulatory properties of Dex-DC in the rat and human experimental systems. After treatment with dexamethasone (Dex), the immunogenicity of Dex-DC was analyzed in T-cell proliferation and two-step hyporesponsiveness induction assays. After carboxyfluorescein diacetate succinimidyl ester labeling, CD4+CD25+ regulatory T-cell expansion was analyzed by flow cytometry, and cytokine secretion was measured by ELISA. In this study, we demonstrate in vitro that rat Dex-DC induced selective expansion of CD4+CD25+ regulatory T cells, which were responsible for alloantigen-specific hyporesponsiveness. The induction of regulatory T-cell division by rat Dex-DC was due to secretion of interleukin (IL)-2 by DC. Similarly, in human studies, monocyte-derived Dex-DC were also poorly immunogenic, were able to induce T-cell anergy in vitro, and expand a population of T cells with regulatory functions. This was accompanied by a change in the cytokine profile in DC and T cells in favor of IL-10. These data suggest that Dex-DC induced tolerance by different mechanisms in the two systems studied. Both rat and human Dex-DC were able to induce and expand regulatory T cells, which occurred in an IL-2 dependent manner in the rat system.

Induced Liver Allograft Immunological Tolerance in Rats by Intramuscular Injection of Recombinant Adeno-Associated Virus–Human Cytotoxic T-lymphocyte-associated Antigen-4 Immunoglobulin (rAAV-hCTLA4Ig)

Induction of liver allograft immunological tolerance was performed in rats by intramuscular injection of recombinant adeno-associated virus-human cytotoxic T-lymphocyte-associated antigen-4 immunoglobulin (rAAV-hCTLA4Ig). Dark Agouti and Lewis rats were liver allograft donors and recipients, respectively, in four groups: (A) syngeneic control, (B) blank control, (C) rAAV-enhanced green fluorescent protein negative control, (D) rAAV-hCTLA4Ig. Gene transfers occurred 6 weeks before transplantation. Group D had a significantly longer liver graft survival time (> 100 days) than groups B (11.9 +/- 1.3 days) and C (11.6 +/- 1.1 days). Groups B and C showed severe rejection responses and large amounts of CD4(+) and CD8(+) T-lymphocyte infiltration, while only a mild response and few T-lymphocytes were observed in group D. There were no significant differences in interleukin-2 and interferon-gamma levels in liver grafts between groups D and C, but there were significant decreases in granzyme B and lymphotoxin beta levels in group D compared with group C. It is concluded that immunological tolerance to liver allograft could be achieved by gene transfer of rAAV-hCTLA4Ig through intramuscular injection.

Induction of Immunological Tolerance in Chicken (Gallus domesticus) to DT40 Cells Stably Transfected with GFP

Induction of Immunological Tolerance in Chicken (Gallus domesticus) to DT40 Cells Stably Transfected with GFP

Role of Adaptive Regulatory T Cells in the Induction of Tolerance to FVIII

Individuals who lack a given protein may never properly develop self tolerance. Thus, the administration of protein therapeutics can lead to undesirable immune responses. A classic example is that patients with Hemophilia A can develop an inhibitory immune response to therapeutic treatments with coagulation factor VIII (fVIII). Several years ago, we developed a B-cell delivered gene therapy based approach to prevent this response and a mouse model to study the mechanisms of the induction and maintenance of immunological tolerance to fVIII inhibitors. This model takes advantage of a knock-in mouse with the transcription factor, FoxP3, in frame with green fluorescent protein (GFP). FoxP3 is considered to be a marker for regulatory T cells (Tregs). The FoxP3-GFP knock-in allows us to follow existing (natural) Tregs and the induction of adaptive Tregs. We have backcrossed this mouse, which expresses GFP in all FoxP3+ Tregs, with the hemophilic mouse, which has an existing deletion in fVIII (E16), for 10 generations. Establishing a mouse that is transgenic for both the FoxP3-GFP fusion and a deletion in fVIII will enhance future clinically oriented experiments to understand how tolerogenic B cells interact with Tregs in a hemophilia system. Lymphocytes from these mice have now been characterized using flow cytometry and confocal microscopy, and analyzed during treatment with tolerogenic B cells. These cells express Treg markers that include, CD25, CTLA-4, GITR and reduced amounts of CD127. However, the population of fVIII antigen-specific cells is small in this mouse model. Thus, it is difficult to detect changes over the natural variation found between mice in a colony, although small changes have been detected. To explore the underlying role of Tregs in tolerance induction, we have bred an ovalbumin (OVA)-specific, T-cell receptor (TCR) transgenic mouse that contains the FoxP3-GFP fusion (FoxP3GFP/DO11.10 and FoxP3GFP/DO11.10/Rag2−/−). Using our B-cell delivered tolerance protocol, we can prevent immunization when an immunologically competent mouse is immunized with OVA in adjuvant. When FoxP3GFP/DO11.10 TCR transgenic mice are treated with OVA-Ig transduced B cells, we found a significant increase in antigen-specific Tregs (p<0.05). Finally, when the same treatment is performed on FoxP3GFP/DO11.10/Rag2−/−, which completely lack natural regulatory cells, we found that FoxP3 was expressed in 4% (p<0.001) of T-cells above background. These cells express markers typical of Tregs. These data strongly support the hypothesis that transduced B cell treatment induces a regulatory phenotype in the antigen-specific T cell population. To extend this system to the hemophilia model, fVIII C2 tetramers will be used to label and isolate antigen-specific T cells during tolerance induction. Additionally, this model opens up avenues of analysis to intra-vital microscopy which gives a true representation of interactions in a live organism. (Supported by NIH RO1 HL061883, NIH T32 HL007698, and a predoctoral fellowship from the American Heart Association.)

CD11c+CD11b+ Dendritic Cells Play an Important Role in Intravenous Tolerance and the Suppression of Experimental Autoimmune Encephalomyelitis

The central role of T cells in the induction of immunological tolerance against i.v. Ags has been well documented. However, the role of dendritic cells (DCs), the most potent APCs, in this process is not clear. In the present study, we addressed this issue by examining the involvement of two different DC subsets, CD11c(+)CD11b(+) and CD11c(+)CD8(+) DCs, in the induction of i.v. tolerance. We found that mice injected i.v. with an autoantigen peptide of myelin oligodendrocyte glycoprotein (MOG) developed less severe experimental autoimmune encephalomyelitis (EAE) following immunization with MOG peptide but presented with more CD11c(+)CD11b(+) DCs in the CNS and spleen. Upon coculturing with T cells or LPS, these DCs exhibited immunoregulatory characteristics, including increased production of IL-10 and TGF-beta but reduced IL-12 and NO; they were also capable of inhibiting the proliferation of MOG-specific T cells and enhancing the generation of Th2 cells and CD4(+)CD25(+)Foxp3(+) regulatory T cells. Furthermore, these DCs significantly suppressed ongoing EAE upon adoptive transfer. These results indicate that CD11c(+)CD11b(+) DCs, which are abundant in the CNS of tolerized animals, play a crucial role in i.v. tolerance and EAE and may be a candidate cell population for immunotherapy of autoimmune diseases.

Dead but Not Deadly

The presence of cells dying by the process of necrosis is a signal for activation of the adaptive immune system and a stimulus for an inflammatory response to protect the organism from the threat that is damaging the dying cells. However, billions of cells in the human immune system die every day by apoptosis, a more orderly physiological form of cell death, and these dying cells are actually anti-inflammatory and promote tolerance of antigens by the immune system. Kazama et al . show that one key difference that influences the immunogenicity of the dying cells is the disruption of mitochondrial function in apoptotic cells and consequent generation of reactive oxygen species (ROS). The authors used an assay of immunogenicity in which mice exposed to dying cells were subsequently exposed to antigens. Treatment of apoptotic cells with the reducing agent dithiothreitol (DTT) prevented their promotion of tolerance, and exposure of necrotic cells to the oxidant hydrogen peroxide made them promote tolerance rather than inflammation. The authors focused on high-mobility group box-1 (HMGB1), a protein that binds chromatin and acts as a transcription factor but also functions as an inflammatory cytokine. Release of HMGB1 had been proposed to be a marker of necrotic death, but Kazama et al . saw release of the protein from both apoptotic and necrotic cells. What differed was the oxidation state of HMGB1. Supernatants from apoptotic cells could promote tolerance, but this effect was prevented if ROS species were neutralized with a scavenger or if oxidation of HMGB1 was prevented by mutation of cysteine residues that likely mediate its response to oxidation. Recombinant human HMGB1 could also eliminate the tolerogenic effect of apoptotic cells if the HMGB1 was first treated with DTT, but not if the HMGB1 was first oxidized with hydrogen peroxide. Peter provides commentary and notes that the studies open the way for exploration of how dendritic cells specifically recognize oxidized HMGB1 and what signaling pathways are activated--work that may allow these new concepts to be exploited to modulate immunological activation in patients. H. Kazama, J.-E. Ricci, J. M. Herndon, G. Hoppe, D. R. Green, T. A. Ferguson, Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity 29 , 21-32 (2008). [PubMed] M. E. Peter, ROS eliminate danger. Immunity 29 , 1-2 (2008). [PubMed]

Reduced frequency of nickel allergy upon oral nickel contact at an early age

From animal studies we know that oral administration of T-dependent antigens before sensitization effectively induces systemic immune unresponsiveness. Such 'oral tolerance' is persistent, dose-dependent, antigen-specific and presumably T suppressor cell-mediated. Oral tolerance induction could be an effective way to prevent undesired T cell-mediated immune functions, such as playing a role in allograft reaction, autoimmune and allergic diseases. In the present study allergic contact hypersensitivity (ACH) to nickel, currently presenting the most frequent contact allergy in man, was chosen to establish the feasibility of oral prevention of undesired T cell-mediated immunity in man. Potentially tolerizing (oral nickel contacts via orthodontic braces) as well as sensitizing (ear piercing) events were studied retrospectively in 2176 patients attending nine European patch test clinics. Patients were interviewed by means of a confidential questionnaire. The results show that ear piercing strongly favoured development of nickel ACH. More importantly, patients having had oral contacts with nickel-releasing appliances (dental braces) at an early age, but only if prior to ear piercing, showed a reduced frequency of nickel hypersensitivity. Frequencies of other hypersensitivities, in particular to fragrance, were not affected. These results support our view that induction of specific systemic immunologic tolerance by timely oral administration of antigens is feasible in man.

IL-10-dependent partial refractoriness to Toll-like receptor stimulation modulates gut mucosal dendritic cell function.

The default response of the intestinal immune system to most antigens is the induction of immunological tolerance, which is difficult to reconcile with the constant exposure to ligands for TLR and other pattern recognition receptors. We showed previously that dendritic cells (DC) from the lamina propria of normal mouse intestine may be inherently tolerogenic and here we have explored how this might relate to the expression and function of Toll-like receptors (TLR). Lamina propria (LP) DC showed higher levels of TLR 2, 3, 4 and 9 protein expression than spleen and MLN DC, with most TLR-expressing DC in the gut being CD11clo, class II MHClo, CD103–, CD11b– and F4/80–. TLR expression by lamina propria DC was low in the upper small intestine and higher in distal small intestine and colon. Freshly isolated lamina propria DC expressed some CD40, CD80, CD86 and functional CCR7. These were up-regulated on CD11clo, but not on CD11chi LP DC by stimulation via TLR. However, there was little induction of IL-12 by either subset in response to TLR ligation. This was associated with constitutive IL-10 production and was reversed by blocking IL-10 function. Thus, IL-10 may maintain LP DC in a partially unresponsive state to TLR ligation, allowing them to have a critical role in immune homeostasis in the gut.

Mechanism of T cell tolerance induction by murine hepatic Kupffer cells

The liver is known to favor the induction of immunological tolerance rather than immunity. Although Kupffer cells (KC) have been indicated to play a role in liver tolerance to allografts and soluble antigens, the mechanisms involved remain unclear. We hypothesized that KCs could promote immune tolerance by acting as incompetent antigen-presenting cells (APC), as well as actively suppressing T cell activation induced by other potent APCs. The expression of antigen presentation-related molecules by KCs was phenotyped by flow cytometry. The abilities of KCs to act as APCs and to suppress T cell activation induced by splenic dendritic cells (DC) were examined by in vitro proliferation assays using CD4(+) OVA-TCR (ovalbumin T cell receptor) transgenic T cells. We found that, compared with DCs, KCs expressed significantly lower levels of major histocompatibility complex (MHC) II, B7-1, B7-2, and CD40. This result is consistent with our observation that KCs were not as potent as DCs in eliciting OVA-specific T cell proliferation. However, KCs isolated from polyinosinic:polycytidylic acid-treated mice expressed significantly higher levels of MHC II and costimulatory molecules than did naïve KCs and could stimulate stronger T cell responses. More importantly, we found that KCs could inhibit DC-induced OVA-specific T cell activation. Further investigation of the underlying mechanism revealed that prostaglandins produced by KCs played an important role. The results ruled out the possible involvement of interleukin-10, nitric oxide, 2,3-dioxygenase, and transforming growth factor beta in KC-mediated T cell suppression. Our data indicate that KCs are a tolerogenic APC population within the liver. These findings suggest that KCs may play a critical role in regulating immune reactions within the liver and contributing to liver-mediated systemic immune tolerance. (HEPATOLOGY 2008.).

Human invariant Vα24+ natural killer T cells acquire regulatory functions by interacting with IL-10–treated dendritic cells

AbstractGlycolipid-reactive Vα24+ invariant natural killer T (iNKT) cells have been implicated in regulating a variety of immune responses and in the induction of immunologic tolerance. Activation of iNKT cells requires interaction with professional antigen-presenting cells, such as dendritic cells (DCs). We have investigated the capacity of distinct DC subsets to modulate iNKT cell functions. We demonstrate that tolerogenic DCs (tolDCs), generated by treatment of monocyte-derived DC with interleukin (IL)-10, induced regulatory functions in human iNKT cells. tolDCs, compared with immunogenic DCs, had reduced capacity to induce iNKT-cell proliferation, but these cells produced large amounts of IL-10 and acquired an anergic phenotype. These anergic Vα24+ iNKT cells were able to potently inhibit allogeneic CD4+ T-cell proliferation in vitro. Furthermore, the anergic Vα24+ iNKT cells could suppress DC maturation in vitro. We conclude that the interaction of iNKT cells with tolDCs plays an important role in the immune regulatory network, which might be exploited for therapeutic purposes.

Decreased numbers of FoxP3-positive and TLR-2-positive cells in intestinal mucosa are associated with improvement in patients with active inflammatory bowel disease following selective leukocyte apheresis

Impaired immunological tolerance to commensal enteric flora is considered one possible pathogenic mechanism of inflammatory bowel disease (IBD). Given that regulatory T cells and Toll-like receptor (TLR)-positive cells are key actors in mucosal immune regulation, we aimed to identify the dynamics of these actors in the intestinal mucosa in relation to clinical improvement following selective leukapheresis treatment. Ten patients with active IBD despite treatment with corticosteroids, immunomodulators, or anti-tumor necrosis factor therapy were assessed by immunohistochemical staining of colorectal mucosal biopsies obtained before and after five sessions (week 7) of granulocyte and monocyte adsorption apheresis (GCAP). The presence of FoxP3-positive regulatory T cells, macrophages, dendritic cells, and TLR-2 and-4 positive cells was determined in relation to short-(week 7) and long-term (week 52) clinical outcome data. Following GCAP, the number of FoxP3-(P = 0.012) and TLR-2 (P = 0.008)-positive cells significantly decreased in biopsies after 7 weeks, in parallel with both clinical improvement at week 7 and a longstanding response after 12 months. Downregulation of FoxP3 and TLR-2 cells in the colorectal mucosa mirrors both short-and long-term improvement in patients with active IBD responding to GCAP. This observation suggests a potential role of these cells in the pathogenesis of IBD and the induction of immunological tolerance in the mucosa.

Induction of Immunologic Tolerance to Myelin Basic Protein Prevents Central Nervous System Autoimmunity and Improves Outcome After Stroke

Animals subjected to an inflammatory insult at the time of stroke are predisposed to the development of an inflammatory autoimmune response to brain. This response is associated with worse neurological outcome. Because induction of immunologic tolerance to brain antigens before stroke onset is associated with improved outcome, we sought to determine whether this paradigm could prevent the deleterious autoimmune response to brain provoked by an inflammatory stimulus at the time of ischemia. Male Lewis rats were tolerized to myelin basic protein (MBP) or ovalbumin by intranasal administration before middle cerebral artery occlusion. At the time of reperfusion, all animals received lipopolysaccharide (1 mg/kg intraperitoneal). Behavioral tests were performed at set time intervals. One month after middle cerebral artery occlusion, lymphocytes from the spleens of MBP-tolerized animals were less likely to evidence an autoimmune response and more likely to evidence a regulatory response (Treg) toward MBP than those from ovalbumin-tolerized animals. Animals that had an inflammatory response toward MBP (a Th1 response) performed worse on behavioral tests than those that did not. Fractalkine, a surrogate marker of inflammation, was elevated in animals with a Th1 response to MBP. These data extend our previous findings and suggest that deleterious autoimmunity to brain antigens can be prevented by prophylactically inducing regulatory T-cell responses to those antigens.

Tolerance-Inducing Immunosuppressive Strategies in Clinical Transplantation

The significant development of immunosuppressive drug therapies within the past 20 years has had a major impact on the outcome of clinical solid organ transplantation, mainly by decreasing the incidence of acute rejection episodes and improving short-term patient and graft survival. However, long-term results remain relatively disappointing because of chronic allograft dysfunction and patient morbidity or mortality, which is often related to the adverse effects of immunosuppressive treatment. Thus, the induction of specific immunological tolerance of the recipient towards the allograft remains an important objective in transplantation. In this article, we first briefly describe the mechanisms of allograft rejection and immune tolerance. We then review in detail current tolerogenic strategies that could promote central or peripheral tolerance, highlighting the promises as well as the remaining challenges in clinical transplantation. The induction of haematopoietic mixed chimerism could be an approach to induce robust central tolerance, and we describe recent encouraging reports of end-stage kidney disease patients, without concomitant malignancy, who have undergone combined bone marrow and kidney transplantation. We discuss current studies suggesting that, while promoting peripheral transplantation tolerance in preclinical models, induction protocols based on lymphocyte depletion (polyclonal antithymocyte globulins, alemtuzumab) or co-stimulatory blockade (belatacept) should, at the current stage, be considered more as drug-minimization rather than tolerance-inducing strategies. Thus, a better understanding of the mechanisms that promote peripheral tolerance has led to newer approaches and the investigation of individualized donor-specific cellular therapies based on manipulated recipient regulatory T cells.

Primary prevention of allergy: avoiding risk or providing protection?

Primary prevention strategies of allergy so far have been aimed to fight allergy causes, by avoiding risk factors and inhibiting their mechanisms of action. The results of trials testing food or airborne allergen avoidance as a prevention strategy were, however, rather disappointing. A reverse approach for primary prevention of allergies aims to facilitate exposure to protecting factors which promote the induction of immunologic tolerance against innocuous antigens. These factors are associated with farming environment and a 'traditional lifestyle', but identification of these factors is quite difficult. Major candidates include food-borne microbes, helminths or their components, which are able to stimulate mucosal immunity, particularly in the gut. Similarly, new preventive and therapeutic strategies are being tested to induce specific food-allergen oral tolerance through the ingestion of progressively increasing doses of the offending food. This shifting of allergy prevention research from avoidance to tolerance induction will hopefully allow us to reverse the epidemic trend of allergy diseases.