We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine
Published Online:https://doi.org/10.2217/imt.11.142

Given the shortage of human organs for transplantation, the waiting lists are increasing annually and consequently so is the time and deaths during the wait. As most immune suppression therapy is not antigen specific and the risk of infection tends to increase, scientists are looking for new options for immunosuppression or immunotolerance. Tolerance induction would avoid the complications caused by immunosupressive drugs. As such, taking into account the experience with autoimmune diseases, one strategy could be immune modulation-induced changes in T-cell cytokine secretion or antigen therapy; however, most clinical trials have failed. Gene transfer of MHC genes across species may be used to induce tolerance to xenogenic solid organs. Other options are induction of central tolerance by the establishment of mixed chimerism through hematopoietic stem cell transplantation and the induction of ‘operational tolerance’ through immunodeviation involving dendritic or Tregs. I propose that, as the recognition and tolerance of proteins takes place in the thymus, this organ should be the main target for immunotolerance research protocols even as early as during the fetal development.

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

References

  • Apostolopoulos V, Lazoura E, Yu M. MHC and MHC-like molecules: structural perspectives on the design of molecular vaccines. Adv. Exp. Med. Biol.640,252–267 (2008).
  • Kruskall MS. The major histocompatibility complex: the value of extended haplotypes in the analysis of associated immune diseases and disorders. Yale J. Biol. Med.63(5),477–486 (1990).
  • Rocha N, Neefjes J. MHC class II molecules on the move for successful antigen presentation. EMBO J.27(1),1–5 (2008).
  • Blanchard N, Shastri N. Coping with loss of perfection in the MHC class I peptide repertoire. Curr. Opin Immunol.20(1),82–88 (2008).
  • Blasczyk R, Wehling J, Kotsch K et al. The diversity of the HLA class I introns reflects the serological relationship of the coding regions. Beitr. Infusionsther. Transfusionsmed.34,231–235 (1997).
  • Solberg OD, Mack SJ, Lancaster AK et al. Balancing selection and heterogeneity across the classical human leukocyte antigen loci: a meta-analytic review of 497 population studies. Hum. Immunol.69(7),443–464 (2008).
  • Starr TK, Jameson SC, Hogquist KA. Positive and negative selection of T cells. Annu. Rev. Immunol.21,139–176 (2003).
  • Krichen H, Sfar I, Jendoubi-Ayed S et al. Genetic polymorphisms of immunoregulatory proteins in acute renal allograft rejection. Transplant. Proc.41(8),3305–3307 (2009).
  • Ferrara JL, Levine JE, Reddy P et al. Graft-versus-host disease. Lancet373(9674),1550–1561 (2009).▪ Excellent review of this phenomenon.
  • 10  Riddell SR, Appelbaum FR. Graft-versus-host disease: a surge of developments. PLoS Med.4(7),E198 (2007).
  • 11  Drakopoulou E, Outram SV, Rowbotham NJ et al. Non-redundant role for the transcription factor Gli1 at multiple stages of thymocyte development. Cell Cycle9(20),4144–4152 (2010).
  • 12  Huseby ES, Kappler JW, Marrack P. Thymic selection stifles TCR reactivity with the main chain structure of MHC and forces interactions with the peptide side chains. Mol. Immunol.45(3),599–606 (2008).
  • 13  Tanchot C, Lemonnier FA, Perarnau B et al. Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science276(5321),2057–2062 (1997).
  • 14  Arens R, Schoenberger SP. Plasticity in programming of effector and memory CD8 T-cell formation. Immunol. Rev.235(1),190–205 (2010).▪ Complete explanation of the CD8 T-cell formation.
  • 15  Lakkis FG. Transplantation tolerance: a journey from ignorance to memory. Nephrol. Dial. Transplant.18(10),1979–1982 (2003).▪▪ High-quality paper explaining transplantation tolerance.
  • 16  Selin LK, Brehm MA. Frontiers in nephrology. heterologous immunity, T cell cross-reactivity, and alloreactivity. J. Am. Soc. Nephrol.18(8),2268–2277 (2007).
  • 17  Ibrahim S, Dawson DV, Sanfilippo F. Predominant infiltration of rejecting human renal allografts with T cells expressing CD8 and CD45RO. Transplantation59(5),724–728 (1995).
  • 18  Gallon L, Gagliardini E, Benigni A et al. Immunophenotypic analysis of cellular infiltrate of renal allograft biopsies in patients with acute rejection after induction with alemtuzumab (Campath-1H). Clin. J. Am. Soc. Nephrol.1(3),539–545 (2006).
  • 19  Daniel C, Nolting J, von BH. Mechanisms of self-nonself discrimination and possible clinical relevance. Immunotherapy1(4),631–644 (2009).
  • 20  Moore DJ, Markmann JF, Deng S. Avenues for immunomodulation and graft protection by gene therapy in transplantation. Transpl. Int.19(6),435–445 (2006).
  • 21  Akst LM, Siemionow M, Dan O et al. Induction of tolerance in a rat model of laryngeal transplantation. Transplantation76(12),1763–1770 (2003).
  • 22  Jones ND, Brook MO, Carvalho-Gaspar M et al. Regulatory T cells can prevent memory CD8- T-cell-mediated rejection following polymorphonuclear cell depletion. Eur. J. Immunol.40(11),3107–3116 (2010).
  • 23  Carvalho-Gaspar M, Jones ND, Luo S et al. Location and time-dependent control of rejection by regulatory T cells culminates in a failure to generate memory T cells. J. Immunol.180(10),6640–6648 (2008).
  • 24  Watson AR, Lee WT. Defective T cell receptor-mediated signal transduction in memory CD4 T lymphocytes exposed to superantigen or anti-T cell receptor antibodies. Cell. Immunol.242(2),80–90 (2006).
  • 25  Hawiger D, Masilamani RF, Bettelli E et al. Immunological unresponsiveness characterized by increased expression of CD5 on peripheral T cells induced by dendritic cells in vivo. Immunity20(6),695–705 (2004).
  • 26  Gallucci S, Matzinger P. Danger signals: SOS to the immune system. Curr. Opin Immunol.13(1),114–119 (2001).
  • 27  Marincek BC, Kuhnle MC, Srokowski C et al. Heat shock protein-antigen fusions lose their enhanced immunostimulatory capacity after endotoxin depletion. Mol. Immunol.46(1),181–191 (2008).
  • 28  Heath WR, Carbone FR. Cross-presentation, dendritic cells, tolerance and immunity. Annu. Rev. Immunol.19,47–64 (2001).
  • 29  Hermiston ML, Xu Z, Majeti R et al. Reciprocal regulation of lymphocyte activation by tyrosine kinases and phosphatases. J. Clin. Invest.109(1),9–14 (2002).
  • 30  Toungouz M, Donckier V, Goldman M. Tolerance induction in clinical transplantation. the pending questions. Transplantation75(Suppl. 9),S58–S60 (2003).
  • 31  Ophir E, Reisner Y. Induction of tolerance in organ recipients by hematopoietic stem cell transplantation. Int. Immunopharmacol.9(6),694–700 (2009).
  • 32  Klonisch T, Drouin R. Fetal-maternal exchange of multipotent stem/progenitor cells: microchimerism in diagnosis and disease. Trends Mol. Med.15(11),510–518 (2009).
  • 33  Zhang C, Wang M, Racine JJ et al. Induction of chimerism permits low-dose islet grafts in the liver or pancreas to reverse refractory autoimmune diabetes. Diabetes59(9),2228–2236 (2010).
  • 34  Dutta P, Burlingham WJ. Microchimerism. tolerance vs. sensitization. Curr. Opin Organ Transplant.16(4),359–365 (2011).
  • 35  Ichinohe T. Long-term feto-maternal microchimerism revisited. Microchimerism and tolerance in hematopoietic stem cell transplantation. Chimerism1(1),39–43 (2010).▪▪ Crucial paper to understand the microchimerism and its relation to tolerance.
  • 36  Prigozhina T, Slavin S. Transplantation of hematopoietic stem cells for induction of unresponsiveness to organ allografts. Springer Semin. Immunopathol.26(1–2),169–185 (2004).
  • 37  Roncarolo MG, Gregori S, Lucarelli B et al. Clinical tolerance in allogeneic hematopoietic stem cell transplantation. Immunol. Rev.241(1),145–163 (2011).
  • 38  Sordi V, Piemonti L. Therapeutic plasticity of stem cells and allograft tolerance. Cytotherapy13(6),647–660 (2011).
  • 39  Sayegh MH, Fine NA, Smith JL et al. Immunologic tolerance to renal allografts after bone marrow transplants from the same donors. Ann. Intern. Med.114(11),954–955 (1991).
  • 40  Getts DR, Shankar S, Chastain EM et al. Current landscape for T-cell targeting in autoimmunity and transplantation. Immunotherapy3(7),853–870 (2011).▪▪ Previous article published in Immunotherapy reinforcing the notions of transplantation and T cells.
  • 41  Sykes M. Mixed chimerism and transplant tolerance. Immunity14(4),417–424 (2001).
  • 42  Andre-Schmutz I, Dal CL, Fischer A et al. Improving immune reconstitution while preventing GvHD in allogeneic stem cell transplantation. Cytotherapy7(2),102–108 (2005).
  • 43  Auletta JJ, Cooke KR. Bone marrow transplantation: new approaches to immunosuppression and management of acute graft-versus-host disease. Curr. Opin Pediatr.21(1),30–38 (2009).
  • 44  Kabelitz D, Janssen O. Antigen-induced death of T-lymphocytes. Front. Biosci.2,D61–D77 (1997).
  • 45  Guillonneau C, Seveno C, Dugast AS et al. Anti-CD28 antibodies modify regulatory mechanisms and reinforce tolerance in CD40Ig-treated heart allograft recipients. J. Immunol.179(12),8164–8171 (2007).
  • 46  Ogawa S, Nitta K, Hara Y et al. CD28 knockout mice as a useful clue to examine the pathogenesis of chronic graft-versus-host reaction. Kidney Int.58(5),2215–2220 (2000).
  • 47  Preston SL, Alison MR, Forbes SJ et al. The new stem cell biology: something for everyone. Mol. Pathol.56(2),86–96 (2003).
  • 48  Leibson PJ. The regulation of lymphocyte activation by inhibitory receptors. Curr. Opin Immunol.16(3),328–336 (2004).
  • 49  Murray NA, Roberts IA. Haemolytic disease of the newborn. Arch. Dis. Child Fetal Neonatal Ed.92(2),F83–F88 (2007).
  • 50  Reid ME. Transfusion in the age of molecular diagnostics. Hematology Am. Soc. Hematol. Educ. Program171–177 (2009).
  • 51  Avent ND, Ridgwell K, Tanner MJ et al. cDNA cloning of a 30 kDa erythrocyte membrane protein associated with Rh (rhesus)-blood-group-antigen expression. Biochem. J.271(3),821–825 (1990).
  • 52  Liumbruno GM, D’Alessandro A, Rea F et al. The role of antenatal immunoprophylaxis in the prevention of maternal–foetal anti-Rh(D) alloimmunisation. Blood Transfus.8(1),8–16 (2010).
  • 53  Fung Kee FK, Eason E, Crane J et al. Prevention of Rh alloimmunization. J. Obstet. Gynaecol. Can.25(9),765–773 (2003).
  • 54  Moise KJ Jr. Management of rhesus alloimmunization in pregnancy. Obstet. Gynecol.112(1),164–176 (2008).
  • 55  Wylie BJ, D’Alton ME. Fetomaternal hemorrhage. Obstet. Gynecol.115(5),1039–1051 (2010).
  • 56  Van DV, I, Chong SS, Cota J et al. Single-cell analysis of the RhD blood type for use in preimplantation diagnosis in the prevention of severe hemolytic disease of the newborn. Am. J. Obstet. Gynecol.172(2 Pt 1),533–540 (1995).
  • 57  Tavian M, Hallais MF, Peault B. Emergence of intraembryonic hematopoietic precursors in the pre-liver human embryo. Development126(4),793–803 (1999).
  • 58  Zambidis ET, Peault B, Park TS et al. Hematopoietic differentiation of human embryonic stem cells progresses through sequential hematoendothelial, primitive, and definitive stages resembling human yolk sac development. Blood106(3),860–870 (2005).
  • 59  Tavian M, Peault B. Embryonic development of the human hematopoietic system. Int. J. Dev. Biol.49(2–3),243–250 (2005).
  • 60  De Miguel MP, Arnalich MF, Lopez IP et al. Epiblast-derived stem cells in embryonic and adult tissues. Int. J. Dev. Biol.53(8–10),1529–1540 (2009).
  • 61  Malgieri A, Kantzari E, Patrizi MP et al. Bone marrow and umbilical cord blood human mesenchymal stem cells. state of the art. Int. J. Clin. Exp. Med.3(4),248–269 (2010).
  • 62  Ariga H, Ohto H, Busch MP et al. Kinetics of fetal cellular and cell-free DNA in the maternal circulation during and after pregnancy. implications for noninvasive prenatal diagnosis. Transfusion41(12),1524–1530 (2001).
  • 63  Leduc M, Aractingi S, Khosrotehrani K. Fetal-cell microchimerism, lymphopoiesis, and autoimmunity. Arch. Immunol. Ther. Exp. (Warsz.)57(5),325–329 (2009).
  • 64  Lleo A, Invernizzi P, Gao B et al. Definition of human autoimmunity – autoantibodies versus autoimmune disease. Autoimmun. Rev.9(5),A259–A266 (2010).
  • 65  Golshayan D. Pascual M. Tolerance-inducing immunosuppressive strategies in clinical transplantation: an overview. Drugs68(15),2113–2130 (2008).
  • 66  Lele SM, Lele MS, Anderson VM. The thymus in infancy and childhood. Embryologic, anatomic, and pathologic considerations. Chest Surg. Clin. N. Am.11(2),233–253 (2001).▪▪ Very complete description of thymus development.
  • 67  Suster S. Rosai J. Histology of the normal thymus. Am. J. Surg. Pathol.14(3),284–303 (1990).
  • 68  Nishino M, Ashiku SK, Kocher ON et al. The thymus. a comprehensive review. Radiographics26(2),335–348 (2006).
  • 69  Parish IA, Heath WR. Too dangerous to ignore: self-tolerance and the control of ignorant autoreactive T cells. Immunol. Cell Biol.86(2),146–152 (2008).
  • 70  Kroczek RA, Mages HW, Hutloff A. Emerging paradigms of T-cell co-stimulation. Curr. Opin Immunol.16(3),321–327 (2004).
  • 71  Coquerelle C, Moser M. DC subsets in positive and negative regulation of immunity. Immunol. Rev.234(1),317–334 (2010).
  • 72  Ralainirina N, Poli A, Michel T et al. Control of NK cell functions by CD4+CD25+ regulatory T cells. J. Leukoc. Biol.81(1),144–153 (2007).
  • 73  Collins A, Littman DR, Taniuchi I. RUNX proteins in transcription factor networks that regulate T-cell lineage choice. Nat. Rev. Immunol.9(2),106–115 (2009).
  • 74  Burnet FM, Fenner F. The production of antibodies. J. Immunol.66,485–486 (1951).
  • 75  Lederberg S. Genes and antibodies. Science129(3364),1649–1653 (1959).
  • 76  Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature172(4379),603–606 (1953).
  • 77  Dixon FJ, Mauer PH. Immunologic unresponsiveness induced by protein antigens. J. Exp. Med.101(3),245–257 (1955).
  • 78  Guerau-de-Arellano M, Martinic M, Benoist C et al. Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity. J. Exp. Med.206(6),1245–1252 (2009).
  • 79  Nossal GJ. The immunological response of foetal mice to influenza virus. Aust. J. Exp. Biol. Med. Sci.35(6),549–557 (1957).
  • 80  Smith RN, Howard JC. Heterogeneity of the tolerant state in rats with long established skin grafts. J. Immunol.125(5),2289–2294 (1980).
  • 81  Egger M, Hauser M, Himly M et al. Development of recombinant allergens for diagnosis and therapy. Front. Biosci. (Elite Ed.)1,77–90 (2009).
  • 82  Li GP, Liu ZG, Qiu J et al. DNA vaccine encoding Der p 2 allergen generates immunologic protection in recombinant Der p 2 allergen-induced allergic airway inflammation mice model. Chin. Med. J. (Engl.)118(7),534–540 (2005).
  • 83  Li AF, Escher A. DNA vaccines for transplantation. Expert Opin. Biol. Ther.10(6),903–915 (2010).
  • 84  Li A, Chen J, Hattori M et al. A therapeutic DNA vaccination strategy for autoimmunity and transplantation. Vaccine28(8),1897–1904 (2010).
  • 85  Mor G, Eliza M. Plasmid DNA vaccines. Immunology, tolerance, and autoimmunity. Mol. Biotechnol.19(3),245–250 (2001).
  • 86  Manner PA, Rubash HE, Herndon JH. Prospectus. Future trends in transfusion. Clin. Orthop. Relat. Res.357,101–115 (1998).
  • 87  Bagnis C, Chiaroni J, Bailly P. Elimination of blood group antigens: hope and reality. Br. J. Haematol.152(4),392–400 (2011).
  • 88  Seifried E, Klueter H, Weidmann C et al. How much blood is needed? Vox Sang.100(1),10–21 (2011).
  • 89  Evans RW, Manninen DL, Dong FB. An economic analysis of pancreas transplantation: costs, insurance coverage, and reimbursement. Clin. Transplant.7(2),166–174 (1993).
  • 90  Elsharif ME, Elsharif EG, Gadour WH. Costs of hemodialysis and kidney transplantation in Sudan: a single center experience. Iran J. Kidney Dis.4(4),282–284 (2010).
  • 91  Mayr M, Fukuda K. Cardiovascular stem cells revisited. J. Mol. Cell. Cardiol.50(2),257 (2011).
  • 92  Sokal EM. From hepatocytes to stem and progenitor cells for liver regenerative medicine: advances and clinical perspectives. Cell Prolif.44(Suppl. 1),39–43 (2011).
  • 93  Gentil MA, Cantarell AC, González Roncero FM et al. Impact of the new drugs in the cost of maintenance immunosuppression of renal transplantation. Is it justified? Nephrol. Dial. Transplant.19(Suppl. 3),III77–III82 (2004).
  • 94  Kwon CH, Lee SK, Ha J. Trend and outcome of Korean patients receiving overseas solid organ transplantation between 1999 and 2005. J. Korean Med. Sci.26(1),17–21 (2011).
  • 95  Torres-Aguilar H, Aguilar-Ruiz SR, González-Pérez G et al. Tolerogenic dendritic cells generated with different immunosuppressive cytokines induce antigen-specific anergy and regulatory properties in memory CD4+ T cells. J. Immunol.184(4),1765–1775 (2010).
  • 96  Harry RA, Anderson AE, Isaacs JD et al. Generation and characterisation of therapeutic tolerogenic dendritic cells for rheumatoid arthritis. Ann. Rheum. Dis.69(11),2042–2050 (2010).
  • 97  Liang S, Ristich V, Arase H et al. Modulation of dendritic cell differentiation by HLA-G and ILT4 requires the IL-6–STAT3 signaling pathway. Proc. Natl Acad. Sci. USA105(24),8357–8362 (2008).
  • 98  Ristich V, Liang S, Zhang W et al. Tolerization of dendritic cells by HLA-G. Eur. J. Immunol.35(4),1133–1142 (2005).
  • 99  Hammerman MR. Organogenetic tolerance. Organogenesis6(4),270–275 (2010).
  • 100  Shin OS, Harris JB. Innate immunity and transplantation tolerance. the potential role of TLRs/NLRs in GVHD. Korean J. Hematol.46(2),69–79 (2011).
  • 101  Favier B, Howangyin KY, Wu J et al. Tolerogenic function of dimeric forms of HLA-G recombinant proteins. A comparative study in vivo. PLoS ONE6(7),E21011 (2011).
  • 102  Naranjo-Gómez M, Raich-Regue D, Onate C et al. Comparative study of clinical grade human tolerogenic dendritic cells. J. Transl Med.9,89 (2011).