OJI  Vol.1 No.2 , September 2011
Molecular and cellular pathways involved in the therapeutic functions of MHC molecules; a novel approach for mitigation of chronic rejection
Abstract: The mutated major histocompatibility complex (MHC) class I that contains donor-type epitopes displayed on recipient-type molecule was show- n to inhibit acute and chronic rejection and in-duce indefinite survival of heterotopic cardiac allografts when administered in combination with a sub-therapeutic dose of cyclosporine (CsA) in a rat transplantation model. To eluci-date the molecular pathways involved in the immunosuppressive effects of the mutated MHC molecule, we analyzedgene and protein expres-sion profile during early and late phase follow-ing post-transplantation. Cytoskeletal structure analysis and expression status of Rho GTPase proteins, vacuolar transport and cytoskeleton regulatory pathways involved in immune re-sponse in T and dendritic cells demonstrated the novel mechanism for the abrogation of chronic rejection. Our studies confirm a new role of Rho GTPase pathway in the modification of T cell motility and infiltration of the graft. We discuss these results within the framework of the most recent literature on MHC and molecu-lar machinery controlling T cell functions and dendritic cell antigen presentation.
Cite this paper: nullSkelton, T. , Kloc, M. and Ghobrial, R. (2011) Molecular and cellular pathways involved in the therapeutic functions of MHC molecules; a novel approach for mitigation of chronic rejection. Open Journal of Immunology, 1, 15-26. doi: 10.4236/oji.2011.12003.

[1]   Bach FH, Amos DB. (1967).Hu-1:major histocompatibility locus in man. Science 156, 1506-1508. doi:10.1126/science.156.3781.1506

[2]   Chinen J, Buckley RH. (2010). Transplantation immunology:solid organ and bone marrow. J Allergy ClinImmunol. 125, S324-335. doi:10.1016/j.jaci.2009.11.014

[3]   Cohen DJ, Loertscher R, Rubin MF, Tilney NL, Carpenter CB, Strom TB. (1984). Cyclosporin: a new immunosuppressive agent for organ transplantation. Ann Intern Med. 10,667-682.

[4]   Hariharan S, Johnson CP, Bresnahan BA, et al. (2000). Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med. 342,605-12. doi:10.1056/NEJM200003023420901

[5]   Cecka JM. (2002). The UNOS Renal Transplant Registry. ClinTranspl. 1-20.

[6]   Safinia N, Afzail B, Atalar K, et al. (2010). T-cell alloimmuntiy and chronic allograft dysfunction. Kidney international. 78 (suppl 119),S2-S12. doi:10.1038/ki.2010.416

[7]   Klein J, Sato A. (2000). The HLA system: second of two parts. N Engl J Med. 343,782-786.

[8]   Marsh SG. (2009). WHO nomenclature committee for factors of the HLA system. Nomenclature for factors of the HLA system, up-date. Tissue Antigens 74,364-366. doi:10.1111/j.1399-0039.2009.01330.x

[9]   Klein J, Sato A. (2000). The HLA system: first two parts. N Engl J Med. 343,702-709.

[10]   Zinkernagel RM, Doherty PC. (1974). Restriction of invitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 248, 701-702. doi:10.1038/248701a0

[11]   Scott A, Sant L, Sant A. (2010). Generation of MHC class II-peptide ligands for CD4 T cell allorecognition of MHC class II mole-cules. CurrOpin Organ Transplant. 15,505-511. doi:10.1097/MOT.0b013e32833bfc5c

[12]   Li X, Raghavan M. (2010). Structure and function of major histocompatability complex class I antigens. CurrOpin Organ Trans-plant.15,499-504. doi:10.1097/MOT.0b013e32833bfb33

[13]   Trivedi HL. (2007).Immunobiology of rejection and adaptation. Transpl Proc. 39,647-652. doi:10.1016/j.transproceed.2007.01.047

[14]   Stern LJ, Wiley DC. (1994). Anitgenic peptide binding by class I and class II histocompatibility proteins. Structure 2,245-251. doi:10.1016/S0969-2126(00)00026-5

[15]   Jensen PE. (2007). Recent advances in antigen processing and presentation. Nature Immunol. 8, 1041-1048. doi:10.1038/ni1516

[16]   Afzail B, Lombardi G, Lechler R. (2008). Pathways of major histocompatability complex allorecognition. CurrOpin Organ Trans-plant. 13, 438-444. doi:10.1097/MOT.0b013e328309ee31

[17]   Jensen PE. (1999). Mechanisms of antigen presentation. ClinChem Lab Med. 37, 179-186. doi:10.1515/CCLM.1999.034

[18]   Elliot T, Williams A. (2005). The optimization of peptide cargo bound to MHC class I molecules by the peptide-loading complex. Immunol Rev. 207,89-99. doi:10.1111/j.0105-2896.2005.00311.x

[19]   Warrens AN, Lombardi G, Lechler RI, et al. (1994). Presentation and recognition of major and minor histocompatability antigens. TransplImmunol. 2, 103-107. doi:10.1016/0966-3274(94)90036-1

[20]   Lechler RI, Batchelor JR. (1982). Restoration of immunogenicity to passenger cell-depleted kidney allografts by the addition of do-nor strain dendritic cells. J Exp Med 155,31-41. doi:10.1084/jem.155.1.31

[21]   Ely LK, Burrows SR, Purcell AW, et al. (2008). T cells behaving badly: structural insights into alloreactivity and autoimmunity. CurrOpinImmunol. 20,575-580. doi:10.1016/j.coi.2008.07.006

[22]   Baker RJ, Hernandez-Fuentes MP, Brookes PA, et al. (2001). The role of the allograft in the induction of donor-specific T cell hy-poresponsiveness. Transplantation 72,480-485. doi:10.1097/00007890-200108150-00020

[23]   Suchin EJ, Langmuir PB, Palmer E, et al. (2001). Qunatifying the frequency of allreactive T cells in vivo: new answeres to an old question. J Immunol. 166,973-981.

[24]   Gras S, Kjer-Nelson L, Chen Z, et al. (2011). The structural bases of direct T-cell allorecognition: implication for T-cell mediated transplant rejection. ImmunolCell Biol. 5, 1-8.

[25]   Crispe IN, Husmann LA, Bevan MJ. (1986). T cell receptor expression and receptor-mediated induction of clonal growth in the de-veloping mouse thymus. High surface beta-chain density is a requirement for functional maturity. Eur J Immunol 16,1283-1288. doi:10.1002/eji.1830161016

[26]   Matzinger P, Bevan MJ. (1977). Hypothesis: why do so many lymphocytes respond to major histocompatability antigens? Cell Im-muol 29,1-5. doi:10.1016/0008-8749(77)90269-6

[27]   Archbold JK, Macdonald WA, Miles JJ, et al. (2006). Alloreactivity between disparate cognate and allogeneic pMHC-I complexes is the result of highly focused, peptide-dependent structural mimicry. J BiolChem 281,34324-34332. doi:10.1074/jbc.M606755200

[28]   Turner SJ, Doherty PC, McClusky J, et al. (2006). Structural derminants of T-cell receptor bias in immunity. Nat Rev Immunol 6,883-894. doi:10.1038/nri1977

[29]   Pietra BA, Wiseman A, Bolwerk A, et al. (2000). CD4 T cell-mediated cardiac allograft rejection requires donor but not host MHC class II. J Clin Invest 106,1003-1010.

[30]   Shoskes DA, Wood KJ. (1994). Indirect presentation of MHC antigens in transplantation. Immunol Today 15,32-38. doi:10.1016/0167-5699(94)90023-X

[31]   Liu Z, Braunstein NS, Suciu FN. (1992). T cell recognition of allopeptides in context of self MHC. J Immunol148,35-40.

[32]   Watts C. (2004). The exogenous pathway for antigen presentation on major histocompatibility complex class II and CD1 molecules. Nat Immunol 5,670-677. doi:10.1038/ni1088

[33]   Cresswell P. (1996). Invariant chain structure and MHC class II function. Cell 84,505-507. doi:10.1016/S0092-8674(00)81025-9

[34]   Inaba K, Turley S, Yamaide F, et al. (1998). Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells. J Exp Med 188,2163-2173. doi:10.1084/jem.188.11.2163

[35]   Fangmann J, Dalchau R, Fabre JW. (1992). Rejection of skin allografts by indirect allorecognition of donor class I major histocom-patabiltiy complex peptides. J Exp Med 175, 1521-1529. doi:10.1084/jem.175.6.1521

[36]   Skelton TS, Tejpal N, Gong Y, et al. (2011). Allochimerich molecules and mechanisms in the abrogation of cardiac allograft rejection. J Heart Lung TransplantEpub, ahead of print.

[37]   Gokmen MR, Giovanna L, Lechler RI. (2008). The importance of the indirect pathway of allorecognition in clinical transplantation. CurrOpinImmunol 20,568-574. doi:10.1016/j.coi.2008.06.009

[38]   Singer JS, Mhoyan A, Fishbein M, et al. (2001). Allochimeric class I MHC molecules prevent chronic rejection and attenuate alloan-tibody response. Transplantation 72,1408-1416. doi:10.1097/00007890-200110270-00014

[39]   Valujskikh A, Lantz O, Celli S, et al. (2002). Cross primed CD8(+) T cells mediate graft rejection via a distinct effector pathway. Nat Immunol 3,844-851. doi:10.1038/ni831

[40]   Kapessidou Y, Habran C, Buonocore S, et al. (2006). The replacement of graft endothelium by recipient-type cells conditions al-lograft rejection mediated by indirect pathway CD4+ T cells. Transplantation 2006; 82:582-591. doi:10.1097/

[41]   Herrera OB, Golshayan D, Tibbott R, et al. (2004). A novel pathway of alloantigen presentation by dendritic cells. J Immunol 173,4828-4837.

[42]   Ridge JP, Di RF, Matzinger PA. (1998). A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393, 474-478. doi:10.1038/30989

[43]   Lee RS, Grusby MJ, Glimcher LH, et al. (1994). Indirect recognition by helper cells can induce donor-specific cytotoxic T lympho-cytes in vivo. J Exp Med 179,865-872. doi:10.1084/jem.179.3.865

[44]   Wise MP, Bemelman F, Cobbold SP, et al. (1998). Linked suppression of skin graft rejection can operate through indirect recognition. J Immunol 161,5813-5816.

[45]   Games DS, Rogers NJ, Lechler RI. (2005). Acquisition of HLA-DR and costimulatory molecules by T cells from allogeneic antigen presenting cells. Am J Transplant 5,1614-1625. doi:10.1111/j.1600-6143.2005.00916.x

[46]   Morelli AE, Larregina AT, Shufesky WJ, et al. (2004). Endocytosis, intracellular sorting and processing of exosomes by dendritic cells. Blood 104,3257-3266. doi:10.1182/blood-2004-03-0824

[47]   Pimenta-Araujo R, Mascarell L, Huesca M, et al. (2001). Embryonic thymic epithelium naturally devoid of APCs is acutely rejected in the absence of indirect recognition. J Immunol 167,5034-5041.

[48]   Calne RY, Sells RA, Pena JR, et al. (1969). Induction of immunologic tolerance by porcine liver allografts. Nature 223,472-476. doi:10.1038/223472a0

[49]   Zeigler SF. (2006). Foxp3: Of mice and men. Ann Rev Immunol 24,209-226. doi:10.1146/annurev.immunol.24.021605.090547

[50]   Toyokawa H, Nakao A, Bailey RJ, Nalesnik MA, et al. (2008). Relative contribution of direct and indirect allorecognition in developing tolerance after liver transplantation. Liver Transpl. 14,346-357. doi:10.1002/lt.21378

[51]   Callaghan CJ, Rouhani FJ, Negus MC, Curry AJ, Bolton EM, Bradley JA, Pettigrew GJ. (2007). Abrogation of antibody-mediated allograft rejection by regulatory CD4 T cells with indirect allospecificity. J Immunol 178, 2221-2228.

[52]   Billingham RE, Brent L, Medawar PB. (2010). Actively acquired tolerance of foreign cell.1953.J Immunol. 184, 5-8. doi:10.4049/jimmunol.0990109

[53]   Sayegh MH, Perico N, Gallon L, et al. (1994). Mechanism of acquired thymichyporesponsiveness to renal allografts. Thymic recognition of immunodominantallo-MHC peptides induces peripheral T cell anergy. Transplantation 58, 125-132. doi:10.1097/00007890-199407270-00001

[54]   Zhou C, Lu R, Lin G, et al. (2011). The latest developments in synthetic peptides with immunoregulatory activities. Peptides 32,408-414. doi:10.1016/j.peptides.2010.10.019

[55]   Krensky AM, Clayberger C. (1997). HLA-derived peptides as novel immunosuppressives. Nephrol Dial Transplant 12,865-878. doi:10.4049/jimmunol.0990109

[56]   Gobrial RM, Hamashima W, Wang M, et al. (1996). Induction of transplantion tolerance by chimeric donor/recipient class I RT1.Aa molecules. Transplantation 62,1002-1010. doi:10.1097/00007890-199610150-00020

[57]   Lisik W, Gong Y, Tejpal N, et al. (2010).Intragraft gene expression profile associated with the induction of tolerance by allochimeric MHC I in the rat heart transplant model. Genesis 1, 8-19.

[58]   Lisik W, Tejpal N, Gong Y, et al. (2009). Down regulation of genes involved in T cell polarity and motility during the induction of heart allograft tolerance by allochimeric MHC I. PlosOne4:e8020. doi:10.1371/journal.pone.0008020

[59]   Skelton TS, Tejpal N, Gong, Y, et al. (2010). Downregulation of RhoA and changes in T cell cytoskeleton correlate with the abrogation of allograft rejection. Transplant Immunol 23,185-193. doi:10.1016/j.trim.2010.06.009

[60]   Wheeler AP, Ridley AJ. (2004). Why three Rho proteins? RhoA, RhoB, RhoC and cell motility. Exp Cell Res 301, 43-49. doi:10.1016/j.yexcr.2004.08.012

[61]   Semiletova N, Shen XD, Baibakov B, et al. (2010). Intensity of transplant chronic rejection correlates with level of graft-infiltrating regulatory cells. J Heart Lung Transplant 29,335-341. doi:10.1016/j.healun.2009.08.003