Targeting MHC Class I Monomers to Dendritic Cells Inhibits the Indirect Pathway of Allorecognition and the Production of IgG Alloantibodies Leading to Long-Term Allograft Survival

Abstract

T cell depletion strategies are an efficient therapy for the treatment of acute rejections and are an essential part of tolerance induction protocols in various animal models; however, they are usually nonselective and cause wholesale T cell depletion leaving the individual in a severely immunocompromised state. So far it has been difficult to selectively delete alloreactive T cells because the majority of protocols either delete all T cells, subsets of T cells, or subpopulations of T cells expressing certain activation markers, ignoring the Ag specificity of the TCR. We have developed a model in which we were able to selectively deplete alloreactive T cells with an indirect specificity by targeting intact MHC molecules to quiescent dendritic cells using 33D1 as the targeting Ab. This strategy enabled us to inhibit the indirect alloresponse against MHC-mismatched skin grafts and hence the generation of IgG alloantibodies, which depends on indirectly activated T cells. In combination with the temporary abrogation of the direct alloresponse, we were able to induce indefinite skin graft survival. Importantly, the targeting strategy had no detrimental effect on CD4+CD25+FoxP3+ T cells, which could potentially be used as an adjunctive cellular therapy. Transplantation tolerance depends on the right balance between depletion and regulation. For the former this approach may be a useful tool in the development of future tolerance induction protocols in non-sensitized patients.

Endogenous dendritic cells mediate the effects of intravenously injected therapeutic immunosuppressive dendritic cells in transplantation

“…[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] To address this issue, we selected as prototypic therapeutic DCs, donor-derived MR-DCs generated in vitro with VD 3 , which restrain the antidonor response and prolong survival of mouse cardiac allografts with efficacy comparable with previously described immature, MR, or alternatively-activated DCs generated by alternative methods. 13,14,[16][17][18][19][21][22][23] In situ targeting of quiescent DCs in secondary lymphoid organs has demonstrated that presentation of model or allo-Ag by immature/ semimature DCs promotes abortive T-cell activation followed by deletional tolerance, [34][35][36][37][38][39] and in some cases, expansion of Treg. [36][37][38] The prevailing idea predicts that a similar phenomenon should occur after systemic administration of immunosuppressive DCs bearing donor-Ag.…”

“…Based on previous studies of in situ targeting of quiescent DCs, the injected MR-DCs should promote abortive/defective activation and partial proliferation of allospecific T cells (1-3 days after Ag delivery) followed by deletional tolerance and, in some models, generation of Treg. [34][35][36][37][38][39] To test whether donor-derived MR-DCs interact directly with donor-reactive CD8 ϩ T cells in vivo, we injected intravenous 5 ϫ 10 6 BALB/c MR-DCs (the DC dose that optimally prolongs allograft survival in our model) into MHC I Ϫ/Ϫ B6 mice (Thy1.2) reconstituted with CFSE-labeled 2C TCRtg CD8 ϩ T cells (Thy1.1), which are specific for BALB/c H-2L d . Because host APCs lack surface MHC I, abortive priming of 2C T cells depends exclusively on contact with the donor-derived MR-DCs.…”

Killer artificial antigen-presenting cells deplete alloantigen-specific T cells in a murine model of alloskin transplantation

“…and/or s.c. injection can elicit vigorous tumor antigen-specific T cell responses in mice [14,35], suggesting the potential for bead-based aAPCs or KaAPCs to interact with T cells in vivo during migration, in the absence of multiple adhesion molecules. In addition, several T cell deletion strategies targeted by MHC tetramers have been developed [19,[36][37][38]. Type I ribosome-inactivating protein saporin-conjugated MHC tetramers can selectively delete more than 75% of target T cells in the spleen after a single injection in a murine model, with minimal bystander killing [37].…”

MHC-Ig Dimers: The next Frontier in Transplantation Immunology

“…The question is how do we surmount chronic rejection? It has been shown that targeting donor MHC peptides to dendritic cells [12] or administering them either intrathymically [13], orally [14], or as donor peptide-pulsed recipient APCs [15] induces tolerance through the indirect pathway of allorecognition. Could MHC-Ig dimers -being chimeric molecules containing donor MHC molecules -act in similar fashion?…”