By instructing key immune system cells to accept transplanted insulin-producing islets, researchers have opened a potentially new pathway for treating type 1 diabetes. If the approach is ultimately successful in humans, it could allow type 1 diabetes to be treated without the long-term complications of immune system suppression.
The technique, reported June 4 in the journal Nature Materials, uses synthetic hydrogel particles (microgels) to present a protein known as the Fas ligand (FasL) to immune system T-effector cells along with the pancreatic islets being transplanted. The FasL protein "educates" the effector cells -- which serve as immune system watchdogs -- causing them to accept the graft without rejection for at least 200 days in an animal model.
The FasL-presenting particles are simply mixed with the living islets before being transplanted into the mice, which suffer from chemically-induced diabetes. The researchers believe the FasL-presenting hydrogels would not need to be personalized, potentially allowing an "off-the-shelf" therapy for the transplanted islets.
Researchers from the Georgia Institute of Technology, University of Louisville and University of Michigan collaborated on the work, which was supported by the Juvenile Diabetes Research Foundation and the National Institutes of Health. A follow up study testing the approach in non-human primates has already begun.
"We have been able to demonstrate that we can create a biomaterial that interrupts the body's desire to reject the transplant, while not requiring the recipient to remain on continuous standard immunosuppression," said Haval Shirwan, the Dr. Michael and Joan Hamilton Endowed Chair in Autoimmune Disease at the University of Louisville School of Medicine and director of the Molecular Immunomodulation Program at the Institute for Cellular Therapeutics at the university. "We anticipate that further study will demonstrate potential use for many transplant types, including bone marrow and solid organs."
In the United States, some 1.25 million persons have type 1 diabetes, which is different from the more common type 2 diabetes. Type 1 diabetes is caused by immune system destruction of the pancreatic islet cells that produce insulin in response to glucose levels. Treatment involves frequent injection of insulin to replace what the islets no longer produce. There is no long-term cure for the disease, though persons with type 1 diabetes have been treated experimentally with islet cell transplants -- which almost always fail after a few years even with strong suppression of the immune system.
"Drugs that allow the transplantation of the islet cells are toxic to them," said Andrés García, the Rae S. and Frank H. Neely Chair and Regents' Professor in Georgia Tech's George W. Woodruff School of Mechanical Engineering. "Clinical trials with transplantation of islets showed effectiveness, but after a few years, the grafts were rejected. There is a lot of hope for this treatment, but we just can't get consistent improvement."
Among the problems, García said, is toxicity to the islet cells from the immune system suppression, which also makes patients more susceptible to other adverse effects such as infections and tumors. Other researchers are exploring techniques to protect the islets from attack, but have so far not been successful.
The research reported in Nature Materials takes a totally different approach. By presenting the FasL protein -- which is a central regulator of immune system cells -- the researchers can prevent the immune system from attacking the cells. Once they are educated at the time of transplantation, the cells appear to retain their acceptance of the transplanted islet cells long after the FasL has disappeared.
"At the time of transplantation, we take the islets that are harvested from cadavers and simply mix them with our particles in the operating room and deliver them to the animal," García explained. "We do not have to modify the islets or suppress the immune system. After treatment, the animals can function normally and are cured from the diabetes while retaining their full immune system operation."
The hydrogels can be prepared up to two weeks ahead of the transplant, and can be used with any islet cells. "The key technical advance is the ability to make this material that induces immune acceptance that can simply be mixed with the islets and delivered. We can make the biomaterial in our lab and ship them to where the transplantation will be done, potentially making it an off-the-shelf therapeutic."
In the experimental mice, the islets were implanted into the kidneys and into an abdominal fat pad. If the treatment is ultimately used in humans, the islets and biomaterial would likely be placed laparoscopically into the omentum, a tissue with significant vasculature that is similar to the fat pad in mice. Garcia's lab has previously shown that it can stimulate blood vessel growth into islet cells transplanted into this tissue in mice.
In future work, the researchers want to see if the graft acceptance can be retained in more complex immune systems, and for longer periods of time. By reducing damage to the cadaver islets, the new technique may be able to expand the number of patients that can treated with available donor cells.
García's lab uses polymer hydrogel particles that are about 150 microns in diameter, about the same size as the islet cells. They engineer the particles to capture the FasL -- a novel recombinant protein developed by Shirwan and Esma S. Yolcu, associate professor of microbiology and immunology at the University of Louisville -- on the particle surface, where it can be seen by the effector cells.
Materials provided by Georgia Institute of Technology. Note: Content may be edited for style and length.
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Kwa kuagiza chembe muhimu za mfumo wa kinga kukubali insulini zinazozalishwa, watafiti wamefungua njia mpya ya kutibu ugonjwa wa kisukari wa aina ya 1. Kama mbinu hiyo itafanikiwa kwa wanadamu, inaweza kuruhusu ugonjwa wa kisukari wa aina ya 1 kutibiwa bila matatizo ya muda mrefu ya kukandamiza mfumo wa kinga. Utafiti huo, uliochapishwa katika jarida la Nature Materials, unatumia chembe za hydrogel za synthetic (microgels) kuwasilisha protini inayojulikana kama Fas ligand (FasL) kwa seli za mfumo wa kinga T-effector pamoja na visiwa vya kongosho vinavyoingizwa. Protini ya FasL hufundisha seli za effector, ambazo hutumika kama walinzi wa mfumo wa kinga, na kuwafanya wakubali graft bila kukataa kwa angalau siku 200 katika mfano wa wanyama. Chembe zinazotoa FasL huchanganywa na visiwa vya kuishi kabla ya kupandikizwa kwenye panya, ambao wanateseka kutokana na ugonjwa wa kisukari unaosababishwa na kemikali. Watafiti wanaamini hydrogels FasL-kuwasilisha haipaswi kuwa binafsi, uwezekano kuruhusu "off-the-shelf" tiba kwa islets kupandikizwa. Watafiti kutoka Chuo Kikuu cha Teknolojia cha Georgia, Chuo Kikuu cha Louisville na Chuo Kikuu cha Michigan walifanya kazi pamoja, na kuungwa mkono na Shirika la Utafiti wa Kisukari cha Vijana na Taasisi ya Kitaifa ya Afya. Utafiti wa kufuatilia unaochunguza mbinu hiyo katika wanyama wasio wanadamu tayari umeanza. "Tumeweza kuonyesha kwamba tunaweza kuunda biomaterial ambayo inakataza hamu ya mwili ya kukataa kupandikiza, wakati hauhitaji mpokeaji kubaki kwenye immunosuppression ya kawaida ya kuendelea, ""alisema Havel Shirwan, Dk Michael na Joan Hamilton Endowed Chair katika Magonjwa ya Autoimmune katika Chuo Kikuu cha Louisville School of Medicine na Mkurugenzi wa Programu ya Immunomodulation ya Molekuli katika Taasisi ya Tiba ya Seli." "Tunatarajia kwamba utafiti zaidi utaonyesha uwezekano wa matumizi ya aina nyingi za upandikizaji, kutia ndani uti wa mgongo wa mifupa na viungo vya mwili." Katika nchi za Ulaya, watu milioni 1.25 wana ugonjwa wa kisukari wa aina ya 1, ambao ni tofauti na ugonjwa wa kisukari wa aina ya 2. Ugonjwa wa kisukari wa aina ya 1 husababishwa na mfumo wa kinga kuharibu seli za visiwa vya kongosho vinavyotengeneza insulini kwa kujibu viwango vya sukari. Matibabu yanahusisha kutiwa sindano ya insulini mara nyingi ili kuchukua mahali pa kile ambacho visiwa hivyo havitokezi tena. Hakuna tiba ya muda mrefu kwa ugonjwa huu, ingawa watu wenye ugonjwa wa kisukari wa aina ya 1 wametibiwa kwa majaribio na upandikizaji wa seli za kisiwa - ambazo karibu kila wakati hushindwa baada ya miaka michache hata na kukandamiza nguvu ya mfumo wa kinga. "Dawa zinazoruhusu kupandikiza seli za visiwa ni sumu kwao, ""alisema Andrés García, Rae S. na Frank H. Neely Mwenyekiti na Profesa wa Regents katika Shule ya Uhandisi ya Mashine ya George W. Woodruff ya Georgia Tech." "Majaribio ya kitiba ya kupandikiza visiwa yalionyesha ufanisi, lakini baada ya miaka michache, viungo hivyo vilikataliwa. Kuna matumaini mengi kwa matibabu haya, lakini hatuwezi kupata uboreshaji thabiti. " "Miongoni mwa matatizo, Garcia alisema, ni sumu kwa seli za kisiwa kutoka kwa kukandamiza mfumo wa kinga, ambayo pia hufanya wagonjwa kuwa na athari nyingine mbaya kama vile maambukizo na uvimbe. """ Watafiti wengine wanachunguza mbinu za kulinda visiwa hivyo kutokana na mashambulizi, lakini hadi sasa hawajafanikiwa. Utafiti uliochapishwa katika gazeti la Nature Materials unachukua mbinu tofauti kabisa. Kwa kuanzisha protini ya FasL - ambayo ni mdhibiti mkuu wa seli za mfumo wa kinga - watafiti wanaweza kuzuia mfumo wa kinga kuishambulia seli. Baada ya kufundishwa wakati wa kupandikiza, seli zinaonekana kuhifadhi kukubalika kwao kwa seli za visiwa vilivyopandikizwa muda mrefu baada ya FasL kutoweka. "Wakati wa kupandikiza, tunachukua visiwa vilivyotokana na maiti na kuvichanganya na chembe zetu katika chumba cha upasuaji na kuzipeleka kwa mnyama,"" García alielezea." "Hatuna haja ya kurekebisha visiwa hivyo au kukandamiza mfumo wa kinga. Baada ya kutibiwa, wanyama hao wanaweza kufanya kazi kwa kawaida na hupona ugonjwa wa kisukari huku mfumo wao wa kinga ukiendelea kufanya kazi kikamili". Hydrogels inaweza kutayarishwa hadi wiki mbili kabla ya kupandikiza, na inaweza kutumika na seli yoyote ya kisiwa. "Ufanisi wa teknolojia ni uwezo wa kutengeneza nyenzo hii ambayo husababisha kukubalika kwa kinga ambayo inaweza kuchanganywa tu na visiwa na kutolewa.""" "Tunaweza kutengeneza vifaa vya kibiolojia katika maabara yetu na kuvipeleka mahali ambapo kupandikiza kutakuwa kufanywa, uwezekano wa kuifanya kuwa tiba ya kawaida. """ Katika panya wa majaribio, visiwa hivyo vilipandikizwa ndani ya figo na ndani ya kifuniko cha mafuta ya tumbo. Ikiwa matibabu hayo yatatumiwa kwa wanadamu, visiwa na vifaa vya kibiolojia vitatumiwa kwa njia ya laparoscopic kwenye omentum, tishu yenye mishipa mikubwa inayofanana na pad ya mafuta ya panya. Maabara ya Garcia ilionyesha hapo awali kwamba inaweza kuchochea ukuaji wa mishipa ya damu katika seli za kisiwa zilizopandikizwa katika tishu hii katika panya. Katika kazi ya baadaye, watafiti wanataka kuona kama kukubalika kwa graft inaweza kuhifadhiwa katika mifumo ya kinga ngumu zaidi, na kwa vipindi vya muda mrefu. Kwa kupunguza uharibifu wa visiwa vya maiti, mbinu hiyo mpya inaweza kupanua idadi ya wagonjwa ambao wanaweza kutibiwa na seli za wafadhili zinazopatikana. Maabara ya Garcia hutumia chembe za polymer hydrogel ambazo zina kipenyo cha karibu microns 150 - karibu ukubwa sawa na seli za kisiwa. "Kama ilivyoelezwa hapo juu, ""FasL"" ni protini mpya ya recombinant iliyoundwa na Dr. Esma S. Yelku, profesa wa microbiology na immunology katika Chuo Kikuu cha Louisville, Marekani, ambayo inaweza kuonekana na seli za effector." Vifaa vilivyotolewa na Taasisi ya Teknolojia ya Georgia. Kumbuka: Maudhui yanaweza kuhaririwa kwa mtindo na urefu. Namba hii ya ukurasa: