Immune Tolerance

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Cytokine regulation of immune tolerance

Cytokine regulation of immune tolerance

It is well-recognized that not all self-reactive T cells are eliminated in the thymus. A traditional viewpoint suggests that peripheral tolerogenic mechanisms (e.g., T cell anergy, exhaustion, deletion, or Treg suppression) must exist in healthy individuals to disarm the remaining self-reactive T cells. In this review, we illustrate a different viewpoint of peripheral tolerance. We believe that cytokines affect T cell activation and differentiation, and in turn regulate immunity and immune tolerance [Figure 1]. The same should hold true for co-stimulatory molecules in the control of T cell activation. Recent advances in the genetics of autoimmune diseases indeed identify numerous risk molecules and genes that contribute to disease susceptibility. Further characterization of risk molecules and their expression and function in vivo will lead to better define the pathogenic pathways of human autoimmunity. This inquiry will also greatly aid in the induction of transplant tolerance.
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Apoptotic cell-linked immunoregulation: implications for promoting immune tolerance in transplantation

Apoptotic cell-linked immunoregulation: implications for promoting immune tolerance in transplantation

Notably, iDCs also produce TGF-β through the phago- cytosis of apoptotic cells and thus contribute to apop- totic cell-linked immune tolerance. iDCs express lower levels of the co-stimulatory molecules CD80, CD86 and MHC II and do not express CD83 [38]. In contrast to mature DCs, iDCs are incapable of initiating effective Th1 and Th2 responses, but they can induce T cell toler- ance. A unique feature of iDCs is their ability to engulf and digest apoptotic cells. Although previous studies emphasized an antigen-presenting function of iDCs after uptake of apoptotic cells, none examined whether the di- gestion of apoptotic cells affected their function of indu- cing adoptive immune responses. Recently, it has been reported that iDCs express TGF-β consequently result- ing in the conversion of naïve CD4 + T cells into Foxp3 + Treg cells [25, 39, 40]. We found that exposure of iDCs to apoptotic cells substantially increased their TGF-β se- cretion and consequently strengthened their ability to convert naïve CD4 + T cells into Foxp3 + Treg cells [34]. This occurred in cell culture as well as in vivo; in mice, iDCs potently engulf apoptotic T cells and selective de- pletion of iDCs with clodronate-liposomes interferes with this increase in CD4 + Foxp3 + Treg cells induced by the CD3-specific antibody. Thus, it would be reasonable to envision that iDCs actively participate in the induc- tion of CD4 + Foxp3 + Treg cells and immune tolerance because of the TGF-β they produce after ingestion of apoptotic cells.
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Durable and sustained immune tolerance to ERT in Pompe disease with entrenched immune responses

Durable and sustained immune tolerance to ERT in Pompe disease with entrenched immune responses

Here, we report the first successful induction of long-term immune tolerance in the setting of an entrenched immune response to a lifesaving therapeutic protein. Like IPD, immunogenicity is known to limit the efficacy and cost-effectiveness of therapeutic proteins for many other conditions. IPD is inher- ently rapidly progressive, with long-term survival dependent on the continued efficacy of ERT. Howev- er, a significant percentage of patients with IPD develop deleterious, life-threatening sustained high-titer antibody responses to ERT that minimize or otherwise abolish its clinical efficacy. Given the existence of well-defined clinical outcome measures, these characteristics make IPD a useful model for readily assess- ing perhaps life-saving therapeutic approaches that have potentially broader clinical implications. Indeed, the 3 patients in this study initially improved clinically following commencement of ERT yet experienced subsequent clinical decline closely associated with HSAT development. While immune tolerance in IPD has been achieved in the ERT-naive setting using a combination of rituximab, methotrexate, and IVIG (20), no regimen to date to our knowledge has been able to induce immune tolerance once an entrenched immune response has developed.
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The expression of selected molecular markers of immune tolerance in psoriatic patients

The expression of selected molecular markers of immune tolerance in psoriatic patients

Background. Psoriasis is a chronic autoinflammatory disease whose underlying molecular mechanisms remain unclear. The disease is mediated by the cells and molecules of both the innate and adaptive immune systems. Some T cell surface molecules, including neuropilin-1 (NRP1), programmed death 1 (PD-1) and the human leukocyte antigen G (HLA-G), are known to play a role in the maintenance of immune tolerance. Objectives. The aim of this study was to investigate HLA-G, NRP1 and programmed cell death gene (PDCD1) mRNA expression in psoriatic patients.

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Goblet cell loss abrogates ocular surface immune tolerance

Goblet cell loss abrogates ocular surface immune tolerance

Altered induction of conjunctival immune tolerance in Spdef-KO mice. Spdef-KO mice that lack GCs have been previously reported to develop ocular surface inflammation and dry eye disease (17). Additional- ly, loss of ocular surface immune tolerance has been observed in experimentally induced mouse dry eye models where GC loss occurs (9, 10). Based on these findings and the altered distribution of APCs in the conjunctiva of the Spdef-KO mice, we compared the ability to induce tolerance to topically applied OVA antigen in WT and Spdef-KO mice using a previously reported protocol with cutaneous delayed type hypersensitivity (DTH) response as the readout (Figure 4A). Compared with unimmunized control mice, both WT and Spdef-KO strains develop a significant DTH response (ear swelling) following s.c. OVA immunization followed by an intradermal ear lobe injection on day 15 (Figure 4B). As previously reported, WT mice developed tolerance to OVA applied topically to the ocular surface; however, tolerance induction was not observed in the Spdef-KO mice (Figure 4B). We also evaluated antigen-specific immune response. Immunization of WT B6 mice increased proliferation of OVA-specific T cells in their spleens, and this was significantly reduced in animals that received OVA drops on the conjunctiva prior to immunization. In con- trast, this decrease in proliferation of OVA-specific T cells was not observed in the Spdef-KO mice (Figure 4C). Similar results were seen in CLN T cells in the B6 mice, but compared with WT mice, the difference in T cell proliferation between the control and mice receiving topical OVA did not reach significance in Spdef-KO mice (Figure 4D). As further evidence in support of defective tolerance induction in the Spdef- KO mice, an increase in CD4 + Foxp3 + cells in the spleen was observed in WT mice topically treated with
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High-dose of intravenous immunoglobulin modulates immune tolerance in premature infants

High-dose of intravenous immunoglobulin modulates immune tolerance in premature infants

IL-10 concentration decreased in both the IVIG and control groups, which were consistent with the IFN- γ in- crease, and IL-17 actually increased through IVIG inter- vention. This could be attributed to two reasons: the premature infant ’ s immature naïve T cells whose function did not develop with their surface markers, and the small samples. The temporary immune tolerance could be a benefit in premature infants for restoring system homeo- stasis; however, the cytokine profile changes, such as in- creasing TGF- β and decreasing IL-6, which also could be correlated with the subsequent bronchopulmonary dyspla- sia [24], which need additional study and documentation. The limitations of this study includes the fact that we did not observe a time period effect of IVIG on Treg cell dis- tribution and cytokine expression profile, which needs fur- ther study in the future.
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A20 as an immune tolerance factor can determine islet transplant outcomes

A20 as an immune tolerance factor can determine islet transplant outcomes

Islet transplantation can restore lost glycemic control in type 1 diabetes subjects but is restricted in its clinical application by a limiting supply of islets and the need for heavy immune suppression to prevent rejection. TNFAIP3, encoding the ubiquitin editing enzyme A20, regulates the activation of immune cells by raising NF-kB signaling thresholds. Here, we show that increasing A20 expression in allogeneic islet grafts resulted in permanent survival for ~45% of recipients, and > 80% survival when combined with subtherapeutic rapamycin. Allograft survival was dependent upon Tregs and was antigen specific, and grafts showed reduced expression of inflammatory factors. Transplantation of islets with A20 containing a loss-of-function variant (I325N) resulted in increased RIPK1 ubiquitination and NF-kB signaling, graft hyperinflammation, and acute allograft rejection. Overexpression of A20 in human islets potently reduced expression of inflammatory mediators, with no impact on glucose-stimulated insulin secretion. Therapeutic administration of A20 raises inflammatory signaling thresholds to favor immune tolerance and promotes islet allogeneic survival. Clinically, this would allow for reduced immunosuppression and support the use of alternate islet sources.
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Cost-utility analysis of immune tolerance induction therapy versus on-demand treatment with recombinant factor VII for hemophilia A with high titer inhibitors in Iran

Cost-utility analysis of immune tolerance induction therapy versus on-demand treatment with recombinant factor VII for hemophilia A with high titer inhibitors in Iran

To reduce these risks and improve QoL, immune tolerance induction (ITI), eg, the regular infusion of FVIII concentrates over a time period ranging from months to years, is usually attempted to overpower high responding (anamnesis) FVIII inhibitors of recent onset and restore normal factor pharmacokinetics. 10,14,15

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Analysis on Immune Tolerance and Resistance Mechanism of Cryptococcus albidus of AIDS Patients with Opportunistic Cryptococci Infection

Analysis on Immune Tolerance and Resistance Mechanism of Cryptococcus albidus of AIDS Patients with Opportunistic Cryptococci Infection

Objective: To explore more about the immune tolerance and drug resistance of white Cryptococci albidus in AIDS patients with opportunistic Cryptococcus infection. Methods: To analyze drug re- sistance of the samples of white Cryptococcus albidus extracted from opportunistic infection AIDS patients in the certain infection area from October 2011 to December 2014. Results: After analyz- ing two samples of Cryptococcus albidus from 885 cases with opportunistic infection, we found that one of the samples do resist to ten common antibiotics. They were fluconazole, flu-cytosine, fluconazole, caspofungin, amphotericin B, MI miconazole, terbinafine, ketoconazole and itracona- zole. The other one was sensitive to voriconazole, but resistant to the rest of the drug. Two strains of bacteria were inoculated into the animals in vivo and their DNA was extracted to carry out the genotyping analysis. The results showed that different degrees of resistance gene amplification bands were found in the 10 kinds of antibiotics. Conclusion: Although there were few opportunis- tic infection Cryptococcus albidus in AIDS patients, it was easy to show its resistance to drugs. Therefore, great attention should be paid to it for the medical workers.
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Immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis I

Immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis I

Successful induction of immune tolerance. The characteristics of the MPS I dogs used in the study are summarized in Table 1. Eleven MPS I dogs were successfully made immune tolerant to rhIDU using the 60-day immunosuppressive regimen (cyclosporine A and azathioprine) coupled with weekly infusions of low-dose (0.056 mg/kg/wk) rhIDU as previously described (17). One addi- tional MPS I dog (El) remained tolerant to rhIDU throughout the study period without immune suppression. All immunosuppres- sives were discontinued by 60 days into the regimen. Low-dose infu- sions were continued for a total of 12 weeks in the original meth- od, and then the dose was ramped up to 0.58 mg/kg/wk rhIDU. A weekly i.v. dose of 0.58 mg/kg provided in a 3-hour infusion is the same dose and regimen approved by the FDA for treatment of MPS I patients. Immune tolerance was defined as a serum anti-idu- ronidase titer of less than 20 OD units/μl, and non-tolerance was any titer above this value. The less than 20 OD units/μl tolerance criterion was operationally defined based upon the limit of the range of low titers achieved with the 60-day tolerance regimen and the in vitro uptake inhibition that showed less than 10% inhibition (17). Tolerant dogs received 14–44 weeks (mean, 24.6 ± 12.3 weeks) of full- or high-dose i.v. rhIDU and had a mean end-study anti- iduronidase antibody titer of 4.23 ± 4.74 OD units/μl, and in gen- eral, the antibody levels showed at most small increases in the early 12-week time frame and remained steadily low thereafter. Twelve MPS I dogs were not tolerant to rhIDU. Nontolerant dogs devel- oped a high mean antibody titer of 376 ± 637 OD units/μl after 9–40 weeks (mean 19.1 ± 7.54 weeks) of full- or high-dose i.v. rhIDU. The titers in these dogs steadily rose over the first 12–16 weeks and continued rising slowly thereafter. Of these nontolerant canines, 6 had intermediate titers of 28.4–113 OD units/μl, with a mean of 66.0 OD units/μl. Five of these 6 dogs had received alter- nate, shorter (21–45 days) tolerance regimens that did not induce complete tolerance as defined here (<20 OD units/μl), but this often resulted in lower titers than in nontolerized canines (30–100 OD units/μl). No dog receiving the originally published 60-day toler- ance regimen failed to become tolerant to rhIDU.
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Immune cell trafficking from the brain maintains CNS immune tolerance

Immune cell trafficking from the brain maintains CNS immune tolerance

In the CNS, no pathway dedicated to immune surveillance has been characterized for preventing the anti-CNS immune responses that develop in autoimmune neuroinflammatory disease. Here, we identified a pathway for immune cells to traffic from the brain that is associated with the rostral migratory stream (RMS), which is a forebrain source of newly generated neurons. Evaluation of fluorescently labeled leukocyte migration in mice revealed that DCs travel via the RMS from the CNS to the cervical LNs (CxLNs), where they present antigen to T cells. Pharmacologic interruption of immune cell traffic with the mononuclear cell-sequestering drug fingo- limod influenced anti-CNS T cell responses in the CxLNs and modulated experimental autoimmune encepha- lomyelitis (EAE) severity in a mouse model of multiple sclerosis (MS). Fingolimod treatment also induced EAE in a disease-resistant transgenic mouse strain by altering DC-mediated Treg functions in CxLNs and disrupting CNS immune tolerance. These data describe an immune cell pathway that originates in the CNS and is capable of dampening anti-CNS immune responses in the periphery. Furthermore, these data provide insight into how fingolimod treatment might exacerbate CNS neuroinflammation in some cases and suggest that focal therapeu- tic interventions, outside the CNS have the potential to selectively modify anti-CNS immunity.
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Working toward immune tolerance in lung transplantation

Working toward immune tolerance in lung transplantation

Enhancing host immune regulation, even without generating durable spe- cific immune tolerance, is a worthwhile goal for clinician-scientists. The notion of prope tolerance was advanced origi- nally to explain success achieved in kid- ney transplantation with the use of Campath-1H (11), an agent which causes a profound deletion of T cells (includ- ing potentially helpful regulatory cells); however, prope tolerance could be a reasonable goal for nondeletional toler- izing therapies in inherently difficult- to-tolerize organs, such as the lung. As a more sophisticated understanding of the unique roles played by graft-infiltrating cells is obtained, immunotherapies can be better tailored to the site-specific biology of the transplanted organ.
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Gene Therapy Approaches To Immune Tolerance Induction In Canine Hemophilia

Gene Therapy Approaches To Immune Tolerance Induction In Canine Hemophilia

first described when it was observed that frequent administration of large doses of FVIII could reduce inhibitor titers over time 91 . Currently, there are many variations of ITI, but they all have in common continuous exposure to FVIII protein via frequent dosing of FVIII, often daily administrations of high-dose FVIII 88-92 . ITI is generally considered to have failed if it has not eradicated inhibitors and restored normal FVIII pharmacokinetics in the circulation 88 . It only succeeds in approximately 2/3 of cases 70,88,90,92 . It is also often followed by long-term prophylaxis, as on-demand FVIII therapy is presumed to increase the risk of relapse 251 . ITI is also quite expensive, costing more than $1M/year on average 97,98 , putting it out of reach of many patients in developing countries. Additionally, alternate hemostatic agents must be used to control or prevent bleeding until the inhibitor titer is low enough to overcome with additional FVIII, which adds to the cost. The ITI protocol imposes a substantial burden on patients, especially pediatric patients who are the majority of the patient population with inhibitors. Repeated FVIII administration often requires a central venous catheter, which adds thrombosis and infection risks 252,253 . While ITI is often successful, there are significant challenges in its implementation and these, combined with its expense, are driving research into alternate methods of inducing immune tolerance to FVIII.
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Viral Infections and Autoimmune Disease: Roles of LCMV in Delineating Mechanisms of Immune Tolerance

Viral Infections and Autoimmune Disease: Roles of LCMV in Delineating Mechanisms of Immune Tolerance

In 1991, a breakthrough in our understanding of the role of viruses in triggering autoimmunity came from two studies published in Cell describing the LCMV-induced model of autoimmune diabetes [10, 11]. Two independent groups led by Zinkernagel and Oldstone showed for the first time, transgenic mice expressing the glycoprotein (GP) or nucleoprotein (NP) of LCMV as a self-antigen in their islets (under the control of the rat insulin promoter [RIP]) can develop diabetes after viral clearance between 10-15 days after infection with LCMV. RIP-LCMV diabetic mice developed predominantly a T-cell (CD8)-mediated acute form of autoimmune diabetes. Interestingly,, autoreactive T cells (and antibodies) were not only specific to LCMV, but also to islet antigens. Thus, a single infection with LCMV led to breakdown of tolerance to islet antigens through mechanisms known today as molecular mimicry (a phenomenon where sequence similarities between foreign and self-peptides result in the cross-activation of autoreactive T or B cells by pathogen-derived antigens) , bystander activation (a phenomenon where T cells specific for an antigen become activated during an immune response against an unrelated antigen), and antigen spreading (a phenomenon in which the immune system expands its response beyond the immunodominant epitopes first recognized by T and B cells, these antigens maybe tissue antigens and not necessarily viral epitopes) in support of the fertile field hypothesis (Figure 1).
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Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis

Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis

It is notable that substantial intraislet HA deposits persisted, despite 4-MU treatment. Since 4-MU works at the level of HA synthesis (rather than clearance or catabolism), we suspect that it may take time for HA at sites of inflammation to disappear. The fact that β cell destruction is nonetheless forestalled sug- gests that 4-MU may also induce qualitative changes in resulting ECM that influence local immune function. Histologic assess- ments may also understate the HA decrease because they mea- sure the area within which HA is deposited and not the quantity of HA there. This is perhaps evident in the difference between the decrease in HA area measured histologically (>25%; Figure Figure 6. 4-MU treatment promotes nondestructive insulitis. (A–D) Insulin staining of representative
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T cells expressing chimeric antigen receptor promote immune tolerance

T cells expressing chimeric antigen receptor promote immune tolerance

Here, we used multiple systems to demonstrate that the introduction and transient expression of a CAR construct in adoptively transferred Tcons or Tregs permitted remarkable experimental control of T cell local- ization and activity. This improved outcomes of experimental disease models in mice, including GvHD, GvT effect, and tissue allograft tolerance. For example, expression of the mAbCAR construct that directed T cell activation modulated the severity of GvHD. mAbCAR Tregs maintain their suppressive phenotype and func- tion (Figure 4), including suppression of Tcon proliferation both in vitro and in vivo. Mice that received CAR T cells directed to activate at the site of the gut (MAdCAM1) showed lethal gut GvHD, while those that received CAR T cells directed to activate mainly within the bone marrow compartment (SDF1) showed less GvHD, without impairing GvT responses or bone marrow engraftment. Thus, directing in vivo–infused Tcons away from GvHD targets (e.g., gut mucosa) results in reduced GvHD lethality. It is striking that tran- sient transfection of a fraction of donor T cells could have a lasting effect on T cell reconstitution and GvHD; this suggests possible ways forward for T cell engineering in hematopoietic cell transplantation paradigms. Figure 4. mAbCAR Tregs retain phenotype and function. (A) mAbCAR Tregs retain FoxP3 expression. Histograms of sample FoxP3 staining (dark blue) in comparison to isotype control (light blue) of FoxP3 + selected Tregs. FoxP3 intranuclear expression in untransfected Tregs, FITC-isotype-mAbCAR
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Immune Tolerance Split between Hepatitis B Virus Precore and Core Proteins

Immune Tolerance Split between Hepatitis B Virus Precore and Core Proteins

anti-HBe (Fig. 11, top panel). Induced anti-HBc/HBe antibody production in TCR/Ag double-Tg mice was examined by in- jecting the 7/16–5 TCR-specific peptide p129-140. High- and low-HBcAg-expressing double-Tg mice could be induced to produce anti-HBc and high HBcAg expression correlated with higher titer. In contrast, only low expressers of the HBeAg could be induced to produce anti-HBe antibody, consistent with the concentration dependence of T-cell tolerance to the secreted HBeAg (Fig. 11, middle panel). The ability to induce anti-HBe antibodies by p129-140 injection in 7/16–5 ⫻ HBe(lo) double-Tg mice indicates that even this low concen- tration of serum HBeAg (10 to 20 ng/ml) is not limiting as an immunogen and further indicates that the lack of anti-HBe production at the higher level of HBeAg is due to tolerance mechanisms as opposed to limiting amounts of antigen. Lastly, adoptive transfer of naive 7/16–5 TCR-Tg spleen cells into HBcAg-Tg recipients elicits efficient anti-HBc antibody pro- duction in high-HBcAg-expressing recipients and lower levels of anti-HBc antibody in low-HBcAg-expressing recipients. In contrast, adoptive transfer of the same number of 7/16–5 TCR-Tg spleen cells into high-HBeAg-expressing Tg recipi- ents elicited no anti-HBe antibody production and only very low anti-HBe antibody production in HBeAg(lo) expresser Tg recipients (Fig. 11, bottom panel). This indicates that serum HBeAg need not be present at birth or even perinatally to function as a tolerogen. Rather, exposure of adult, naive 7/16–5 TCR-Tg T cells to circulating HBeAg for a relatively brief period of time in the HBeAg-Tg recipients is sufficient to render the T cells tolerant or at least incapable of mediating FIG. 9. Induced seroconversion in 7/16–5 TCR ⫻ HBc and HBeAg
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Recombinant Lactococcus lactis can make the difference in antigen-specific immune tolerance induction, the Type 1 Diabetes case

Recombinant Lactococcus lactis can make the difference in antigen-specific immune tolerance induction, the Type 1 Diabetes case

lifestyle [97,98]. The manifestations of these diseases come in a wide variety, from “unpleasant” to “life threa- tening when left untreated” . Despite our growing mechanistic understanding, the current standard of care remains unsatisfactory in many cases. Shortcomings range from partial and temporal relief to being asso- ciated with highly undesirable, widespread toxic side effects. It will be necessary to harness our molecular immunological understanding in order to develop medi- cation that can reach the suitable outcome: Ag-specific tolerance induction devoid of side effects. Oral toler- ance, a system that manages the discrimination between friend and foe in the intestine, is one possible entry into this field. However it remains largely untapped because of practical and technological hurdles. In prophylactic settings, clear demonstration of Ag-specific oral toler- ance induction has been given in experimental animals. It however remains very difficult to deliver sufficient amounts of high quality Ag to the human intestine. Rather than being merely preventive, L. lactis Ag-delivery has shown suitable to support intervention strategies in Ag-driven immune diseases. With recombinant L. lactis we avail of the technological tools to bridge between our molecular understanding and the practicalities of human medicine. We can engineer L. lactis to produce (auto-) Ags and immune modulatory factors and genetic engi- neering is such that it is safe to use. Large scale GMP manufacturing has been established and quality controls, both critical components for clinical experimentation under ICH guidelines, are in place. All this has been shown necessary and sufficiently elaborated to allow suc- cessful completion of the regulatory approval process. We now find ourselves at a pivotal point: we have the tools and experience to allow recombinant L. lactis to make a difference in healthcare by helping out people suffering from prominent but largely unmet medical needs.
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A Golden Anniversary: Cattle Twins and Immune Tolerance

A Golden Anniversary: Cattle Twins and Immune Tolerance

RAY OWEN, a postdoctoral fellow in the laboratory and already interested in blood groups of cattle twins, thought they would provide an interesting opportunity for blood [r]

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Poly  and autoreactivity of HIV 1 bNAbs: implications for vaccine design

Poly and autoreactivity of HIV 1 bNAbs: implications for vaccine design

In light of the role that immunological tolerance plays in barring the generation of many bNAbs, there are at least two potential strategies for a universal HIV-1 vac- cine. One tactic is to work within the constraints of tol- erance controls to elicit only those types of bNAbs not proscribed by immune tolerance. The second approach would be to design an immunization regimen that mod- ulates or “breaks” tolerance to gain access to bNAb pre- cursors in the forbidden repertoire. The former strategy, unlike the latter, carries no additional risk of developing autoimmune disease, and therefore is likely to face fewer barriers to regulatory approval and wide use. However, the potential shortcoming of this method is that it must achieve neutralization by targeting only a subset of vul- nerable epitopes. In consequence, bNAbs would have to arise from an even smaller pool of already rare precur- sors. This limitation could further confound vaccination efforts, since precursor cell frequency may be an impor- tant determinant of B-cell competitiveness in anti-Env humoral responses [68, 69], and variability in the human BCR repertoire might preclude the generation of cer- tain bNAb lineages in individuals lacking the required V-, D-, or J-gene allelic variants [12, 67]. However, these remain open questions and are potentially surmountable obstacles.
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