Induction of Transplant Tolerance with Immunodominant Allopeptide-pulsed Host Lymphoid and Myeloid Dendritic Cells

Abstract

We have studied the effects of adoptive transfer of host thymic dendritic cells pulsed with immunodominant WF Class I peptide 5 (residues 93-109) on cardiac allograft survival in the WF-to-ACI rat combination. Our results showed that, whereas intrathymic inoculation of WF peptide 5-pulsed ACI thymic dendritic cells alone on day ª7 did not prolong graft survival, similar treatment combined with 0.5 mL antilymphocyte serum (ALS) led to 100% permanent acceptance (Ͼ 200 d) of donor-specific cardiac allografts. Extension of our study to systemic administration of peptide 5-pulsed host thymic dendritic cells confirmed that intravenous injection of peptide 5-pulsed self thymic dendritic cells combined with ALS transient immunosuppression resulted in 100% permanent donor-specific graft survival (Ͼ 200 d). These results were reproducible in a clinically relevant model using intravenous injection of peptide-pulsed host myeloid dendritic cells. In contrast, thymectomy prior to adoptive transfer of peptide-pulsed host dendritic cells resulted in acute graft rejection at times equivalent to rejection in thymectomized controls. The long-term unresponsive recipients challenged with second-set grafts accepted permanently (Ͼ 100 d) donor-type (WF) but not third party (Lewis) cardiac allografts. This study suggests that intravenous administration of genetically engineered dendritic cells expressing donor MHC molecules has the potential of inducing transplant tolerance.

Immature rat myeloid dendritic cells generated in low-dose granulocyte macrophage-colony stimulating factor prolong donor-specific rat cardiac allograft survival

“…Recent studies suggest that DCs ultimately present Ag in either an immunogenic or tolerogenic manner according to whether they are or are not differentiated into stimulatory or inhibitory phenotype and function (9,19). On the basis of our previous studies demonstrating that the adoptive transfer of P5-pulsed host or donor myeloid or thymic DC induces T-cell tolerance (20,21), we hypothesized that a distinct DC subset present in the peripheral circulation is committed to induction and possibly maintenance of T-cell tolerance. To test this hypothesis, we examined the effects of iMDCs and mMDCs on allogeneic T-cell responses in coculture studies.…”

Role of CD4+CD25+ regulatory T cells from naive host thymus in the induction of acquired transplant tolerance by immunization with allo-major histocompatibility complex peptide.1

“…ALLOGRAFT SURVIVAL AND PREVENTING CHRONIC ALLOGRAFT VASCULOPATHY 1 MASAYUKI SHO, 2,3,5 HIROSHI HARADA, 2 DAVID M. ROTHSTEIN, 4 AND MOHAMED H. SAYEGH 2,3,6 Background. CD45RB is a potent immunomodulatory target to achieve long-term allograft survival.…”

“…Furthermore, the higher and lower molecular weight isoforms are differentially distributed on subsets of T cells that have distinct functions (3,5). Although the exact function of each isoform remains unclear, CD45RB is best characterized in mice and its function seems to be highly regulated and dynamic during T-cell activation (3,6).…”

“…To avoid such problems, we explored the use of the clinically relevant intravenous (IV) route; we recently demonstrated that adoptive transfer of host DC loaded in vitro with a single immunodominant class I allopeptide induced robust acquired tolerance to cardiac and islet allografts (6,7). We also demonstrated that adoptive transfer of in vivo allo-MHC peptideprimed thymic DC, with robust in vitro allostimulatory ability, induced donor-specific tolerance to islets in syngeneic secondary hosts (8).…”

Suppressive dendritic cells as a tool for controlling allograft rejection in organ transplantation: Promises and difficulties

“…When allopeptide-pulsed DCs were injected combined with antilymphocyte serum, 100% permanent acceptance of allografts was obtained in rats [61]. In other experiments DCs were inhibited in their maturation and effector function by rapamycin.…”