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| − | <title>Description</title>
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| − | <h1> <span class="Tspeacial">D</span>escription </h1>
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| − | <img src="https://static.igem.org/mediawiki/2017/0/05/T--TECHNION-ISRAEL--allergies_words.png" class="cover" alt="" style= "width:580px ; margin: auto;">
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| − | <ul class="sidelist hidden-sm hidden-xs" style="width:auto; padding-top:0px;">
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| − | <li> <a class="cell" href="#pr" > The Problem </a> </li>
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| − | <li> <a class="cell" href="#im" > The Immune System </a> </li>
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| − | <li> <a class="cell" href="#imt"> Immune Tolerance </a> </li>
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| − | <li> <a class="cell" href="#de" > How autoimmune diseases and allergies develop </a> </li>
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| − | <li> <a class="cell" href="#cu" >Current Treatment Options </a> </li>
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| − | <li> <a class="cell" href="#so" >Our Solution </a> </li>
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| − | <li> <a class="cell" href="#vi" >Vision </a> </li>
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| − | <h3 id="pr"> The Problem </h3>
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| − | Autoimmune diseases and allergies are on the rise. Scientists have developed many theories as to why this is happening: The hygiene
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| − | hypothesis
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| − | <a href="#ref1" original-title>[1] </a>
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| − | increasing usage of antibiotics, certain ubiquitous drugs and more. Regardless of the cause, an estimated 73 million people currently suffer from these diseases in the United States alone. With over $150 billion
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| − | <sup id = "cite ref-2 " class ="reference">
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| − | <a href="#ref2" original-title>[2] </a>
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| − | spent annually on health care for autoimmune diseases and allergies, this dire problem is quickly becoming untenable.
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| − | <h3 id="im"> The Immune System </h3>
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| − | The immune system is a complex network of tissues, cells, and organs working in tandem to protect our bodies from disease. The Hematopoietic Stem Cell (HSC) is a multipotent, self-renewing, progenitor cell. All differentiated immune and blood cells arise from HSCs that exist in the bone marrow.
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| − | <p style="text-align:center;"> <strong>Figure 1: </strong> Hematopoietic stem cell differentiation tree</p>
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| − | <h3 id="imt"> Immune Tolerance </h3>
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| − | Immune tolerance is the lack of an immunological reaction to the presence of specific substances or tissues that have the capacity to induce an immune response.
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| − | Tolerance is maintained by two mechanisms: Central Tolerance and Peripheral Tolerance. Central Tolerance occurs in the primary lymphoid organs, namely the bone marrow cavities and the thymus, where immature B and T cells, respectively, develop. High affinity interaction between immature lymphocytes and antigens/epitopes present in the bone marrow, or thymus, leads to negative selection, and inactivation, of these reactive immune cells <strong>(Figure 2)</strong>.
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| − | Peripheral Tolerance occurs in the immune periphery, after B and T cells exit the primary lymphoid organs, and is mediated by complex and varied interactions with antigen and other immune cells.
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| − | <p style="text-align:center;"> <strong>Figure 2: </strong> Central Tolerance within the bone marrow
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| − | Immature immune cells within the bone marrow undergoing selection. The red cell recognizes auto-antigen and as a result undergoes apoptosis. The orange immune cell does not recognize auto-antigen and is allowed to complete maturation
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| − | <h3 id="de"> How autoimmune diseases and allergies develop </h3>
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| − | The development of immune disease begins with loss of tolerance. In autoimmune disease there is a loss of tolerance to “self” <strong>(Figure 3)</strong> whereas in allergic reactions there is loss of tolerance to specific external antigens which are harmless. This loss of tolerance is referred to as sensitization. The exact mechanism through which tolerance is lost is still being investigated, and there appear to be multiple pathways involved in the onset of disease.
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| − | <p style="text-align:center;"> <strong>Figure 3: </strong>Disease causing immune cell escaping into the bloodstream
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| − | An immature B-cell capable of recognizing auto-antigen somehow manages to mature and escape into the blood stream. This cell will potentially go on to cause the onset of autoimmune disease
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| − | <h3 id="cu"> Current Treatment Options</h3>
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| − | <p>Many treatments for both autoimmune disease
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| − | <sup id = "cite ref-3 " class ="reference">
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| − | <a href="#ref3" original-title>[3] </a>
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| − | </sup>
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| − | and allergies,
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| − | <sup id = "cite ref-4 " class ="reference">
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| − | <a href="#ref4" original-title>[4] </a>
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| − | such as immunosuppression and desensitization, have been attempted with varying degrees of success, but have largely been ineffective at curbing the prevalence of these conditions. A single treatment modality for immune disorders has yet to be developed. Whilst allergic reactions and the many autoimmune diseases are quite distinct in their presentation and pathophysiology, they both stem from the improper, or unnecessary, activation of the immune system. This common etiology allows hope that one day a single treatment may be sufficient to cure or prevent both types of disease.
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| − | <h3 id="so"> Our Solution</h3>
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| − | <p>We intend to design a preventative treatment for allergies and autoimmune disease. Through genetic engineering and subsequent transfusion of hematopoietic stem cells we hope to induce widespread and continuous immune tolerance towards specific antigens that are known causes of allergic and autoimmune
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| − | disease
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| − | <sup id = "cite ref-5 " class ="reference">
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| − | <a href="#ref5" original-title>[5] </a>
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| − | <a href="#ref6" original-title>[6] </a>
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| − | <sup id = "cite ref-7 " class ="reference">
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| − | <a href="#ref7" original-title>[7] </a>
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| − | </sup>. By utilizing the natural mechanism of Central Tolerance we intend to “educate” the immune system and make it tolerant to specifically targeted antigens. To do this, we are creating a plasmid based platform that will induce hematopoietic stem cells, and their differentiated lineages, to display target antigen on their membrane with the goal of inducing immune tolerance <strong>(Figure 4)</strong>. While the specific antigens we are working on represent only a fraction of the existing diseases and allergies, they serve as proof of concept for a system that we hope will be modular, and effective enough to prevent many more autoimmune and allergic diseases.
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| − | <p style="text-align:center;"> <strong>Figure 4: </strong> Hematopoietic Stem Cell induced to present antigen on its surface
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| − | after transfection with the ToloGen plasmid and genomic integration, the HSC expresses the desired epitopes on its membrane.
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| − | <h3 id="so"> Prevention is the key</h3>
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| − | <p>
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| − | Immunological memory poses a unique problem for HSC based gene therapy. Induction of tolerance will ideally prevent the maturation of harmful B and T cells, but the mechanisms involved do not directly affect existing plasma, and memory, immune cells. Only extreme and dangerous conditioning regiments
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| − | <sup id = "cite ref-8 " class ="reference">
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| − | <a href="#ref8" original-title>[8] </a>
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| − | can eradicate these cells, and this would be unacceptable in a preventative treatment. Thus, patients already sensitized to self-antigen or external allergens will most likely not be cured, and will almost certainly reject any transplanted cells that present such antigens. For this reason we have chosen to focus on prevention, a fundamentally different and novel method for contending with autoimmune and allergic diseases. The ideal candidates for our proposed treatment are newborn babies who have limited immunological memory and development. HSCs can be harvested from cord blood, genetically engineered in a closed environment cell processing system (Link to integrated HUMAN PRACTICE), and transfused back into the child, all within 2-3 days. Finally, after 2-4 weeks, the genetically engineered HSCs will be induced to display the chosen antigens, engendering immune tolerance towards these epitopes.
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| − | <p style="text-align:center;"> <strong>Figure 5: </strong> ToloGen Treatment Strategy
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| − | 1. Cord blood is harvested from new born babies. 2. CD34+ HSCs are isolated from the cord blood using magnetic beads and centrifugation. 3. The HSCs are electroporated with the ToloGen plasmid. 4. The HSCs are transfused back into the baby.
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| − | <h3 id="vi">Vision</h3>
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| − | <p>
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| − | In the 20th century it is estimated that smallpox killed over 500,000,000 people. In 1980 the World Health Organization declared smallpox eradicated
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| − | <sup id = "cite ref-9 " class ="reference">
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| − | <a href="#ref9" original-title>[9] </a>
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| − | </sup>. What was once unimaginable had been accomplished, the disease that had killed more people than all human wars put together, was destroyed. This amazing feat was not accomplished with a miracle cure, a previously unknown panacea, but with a vaccine. Sometimes an ounce of prevention, rather than a pound of cure, is the key. Autoimmune and allergic diseases pose an ever-growing medical and fiscal disaster. It is our hope that this research will help lead the way towards a new treatment paradigm for autoimmune and allergic disease. A paradigm founded on prevention.
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| − | </p>
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| − | The children of tomorrow will never know the misery wrought upon mankind by the smallpox virus. We dream of a day when they will never know the misery of autoimmune diseases and allergies.
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| − | <div class= "references">
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| − | <ol>
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| − | <li id="ref1">Okada, H., et al. "The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update." <i>Clinical & Experimental Immunology </i>160.1 (2010): 1-9.</li>
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| − | <li id="ref2"> <i> http://www.mdmag.com/medical-news/autoimmune-diseases-cost-us-more-than-100-billion-annually <br> http://www.aafa.org/page/allergy-facts.aspx </i></li>
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| − | <li id="ref3">Rosenblum, Michael D. et al. “Treating Human Autoimmunity: Current Practice and Future Prospects.” <i> Science translational medicine </i>4.125 (2012): 125sr1. PMC. Web. 18 June 2017.</li>
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| − | <li id="ref4">Holgate, Stephen T., and Riccardo Polosa. "Treatment strategies for allergy and asthma."<i> Nature Reviews Immunology </i>8.3 (2008): 218-230.</li>
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| − | <li id="ref5">Baranyi, U., et al. "Persistent molecular microchimerism induces long‐term tolerance towards a clinically relevant respiratory allergen." <i>Clinical & Experimental Allergy </i>42.8 (2012): 1282-1292.</li>
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| − | <li id="ref6">Pilat, Nina, and Thomas Wekerle. "Transplantation tolerance through mixed chimerism."<i> Nature Reviews Nephrology</i> 6.10 (2010): 594-605.</li>
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| − | <li id="ref7">Alderuccio, Frank, et al. "Hematopoietic stem cell gene therapy as a treatment for autoimmune diseases." <i>Molecular pharmaceutics </i>8.5 (2011): 1488-1494.</li>
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| − | <li id="ref8">Alexander, T., et al. "Resetting the immune system with immunoablation and autologous haematopoietic stem cell transplantation in autoimmune diseases." <i> Clin Exp Rheumatol </i>34.4 Suppl 98 (2016): S53</li>
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| − | <li id="ref9">Koplow, David A. Smallpox: the fight to eradicate a global scourge. Univ of California Press, 2004.</li>
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