Pancreatic islet transplantation remains a promising approach to the treatment of type 1 diabetes. Unfortunately, graft failure continues to occur because of immunologic rejection, despite the use of potent immunosuppressive agents. It is therefore reasoned that induction of peripheral tolerance by the use of self-dendritic cells (DCs) as a vehicle to deliver specific target antigens to self-T-cells without ex vivo manipulation of the recipient is an attractive strategy in the treatment of type 1 diabetes. The finding that intrathymic inoculation of an immunodominant WF major histocompatibility complex (MHC) Class I (RT1.A(u)) peptide five (P5) or P5-pulsed host myeloid DCs induces acquired thymic tolerance raises the possibility that adoptive transfer of allopeptide-primed host myeloid or lymphoid DCs might induce transplant tolerance. To address this hypothesis, we studied the effects of intravenous transfer of in vitro P5-pulsed syngeneic myeloid DCs or in vivo P5-primed syngeneic lymphoid (thymic) DCs on islet survival in the WF-to-ACI rat combination. In vivo primed thymic DCs isolated from ACI rats given intrathymic inoculation of P5 for 2 days were capable of in vitro restimulation of in vivo P5-primed T-cells (memory cells). In the first series of studies, we showed that intravenous-like intrathymic-inoculation of in vitro P5-pulsed host myeloid DCs induced donor-specific permanent acceptance of islets in recipients transiently immunosuppressed with antilymphocyte serum (ALS). We next examined whether thymic DCs isolated from animals that had been previously intrathymically inoculated with P5 could induce T-cell tolerance. The results showed that intravenous adoptive transfer of in vivo P5-primed thymic DCs led to donor-specific permanent acceptance of islets in recipients transiently immunosuppressed with ALS. This finding suggested that the thymic DCs take up and present P5 to developing T-cells to induce T-cell tolerance, thus providing evidence of a direct link between indirect allorecognition and acquired thymic tolerance. The second series of studies examined the mechanisms involved in this model by exploring whether in vivo generation of peptide-specific alloreactive peripheral T-cells by intravenous inoculation of P5-pulsed self-DCs was responsible for the induction of T-cell tolerance. Intrathymic inoculation of splenic T-cells obtained from syngeneic ACI rats primed with intravenous injection of P5-pulsed DCs with a high in vitro proliferative response to P5 in the context of self-MHC induced donor-specific permanent acceptance of islets from WF donors. In addition, the clinically relevant model of intravenous injection of P5-activated T-cells combined with transient ALS immunosuppression similarly induced transplant tolerance, which was then abrogated by thymectomy of the recipient before intravenous injection of the activated T-cells. These data raise the possibility that circulation of peptide-activated T-cells to the host thymus plays a role in the induction and possibly the maintenance of T...

Our data confirming the immunoregulatory effect of immature DCs indicate that induction of transplant tolerance by iMDCs is partly dependent on in vivo generation of regulatory T cells. This finding suggests that immunization with immature donor DCs has therapeutic potential for the induction of transplant tolerance and treatment of autoimmune diseases.

These findings provide the first formal evidence directly linking reentry of in vivo alloMHC peptide-activated T cells to the thymus with the induction and possibly maintenance of acquired antigen-specific tolerance. Our results suggest that the thymus is open to a two-way traffic with the periphery and may function as a repository of immunological memory.

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 -7 did not prolong graft survival, similar treatment combined with 0.5 mL antilymphocyte serum (ALS) led to 100% permanent acceptance (> 200d) 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 (> 200d). 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 (> 100d) 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.

Our results do not support the recent reports suggesting that HIV infection is associated with poorly differentiated, aggressive disease with poor survival outcome. It remains unclear if breast carcinoma is directly linked to HIV infection.