Biomedical subjects

Angus W Thomson

Publications and source records attributed to Angus W Thomson.

At least 19 recordsLinked to original sources

PubMed2006

"Alternatively activated" dendritic cells preferentially secrete IL-10, expand Foxp3+CD4+ T cells, and induce long-term organ allograft survival in combination with CTLA4-Ig.

In this study, we propagated myeloid dendritic cells (DC) from BALB/c (H2(d)) mouse bone marrow progenitors in IL-10 and TGF-beta, then stimulated the cells with LPS. These "alternatively activated" (AA) DC expressed lower TLR4 transcripts than LPS-stimulated control DC and were resistant to maturation. They expressed comparatively low levels of surface MHC class II, CD40, CD80, CD86, and programmed death-ligand 2 (B7-DC; CD273), whereas programmed death-ligand 1 (B7-H1; CD274) and inducible costimulatory ligand expression were unaffected. AADC secreted much higher levels of IL-10, but lower levels of IL-12p70 compared with activated control DC. Their poor allogeneic (C57BL/10; B10) T cell stimulatory activity and ability to induce alloantigen-specific, hyporesponsive T cell proliferation was not associated with enhanced T cell apoptosis. Increased IL-10 production was induced in the alloreactive T cell population, wherein CD4+Foxp3+ cells were expanded. The AADC-expanded allogeneic CD4+CD25+ T cells showed enhanced suppressive activity for T cell proliferative responses compared with freshly isolated T regulatory cells. In vivo migration of AADC to secondary lymphoid tissue was not impaired. A single infusion of BALB/c AADC to quiescent B10 recipients induced alloantigen-specific hyporesponsive T cell proliferation and prolonged subsequent heart graft survival. This effect was potentiated markedly by CTLA4-Ig, administered 1 day after the AADC. Transfer of CD4+ T cells from recipients of long-surviving grafts (>100 days) that were infiltrated with CD4+Foxp3+ cells, prolonged the survival of donor-strain hearts in naive recipients. These data enhance insight into the regulatory properties of AADC and demonstrate their therapeutic potential in vascularized organ transplantation.

Abatacept↗

PubMed2006

Transgenic galectin-1 induces maturation of dendritic cells that elicit contrasting responses in naive and activated T cells.

Dendritic cells (DC) are professional APC that control the balance between T cell immunity and tolerance. Genetic engineering of DC to regulate the outcome of the immune response is an area of intense research. Galectin (gal)-1 is an endogenous lectin that binds to glycoproteins and exerts potent regulatory effects on T cells. Consequently, gal-1 participates in central deletion of thymocytes and exerts therapeutic effects on experimental models of T cell-mediated autoimmune disorders and graft-vs-host disease. Together, these observations strongly indicate that engineering DC to express transgenic (tg) gal-1 may be beneficial to treat T cell-mediated disorders. In this study, we have investigated the impact of the expression of high levels of tg gal-1 on maturation/activation of DC and on their T cell stimulatory function. Murine DC were transduced with a recombinant adenovirus encoding hu gal-1 (gal-1-DC). Tg gal-1 was exported by a nonclassical pathway through exosomes and was retained on the DC surface inducing segregation of its ligand CD43. Expression of tg gal-1 triggered activation of DC determined by induction of a more mature phenotype, increased levels of mRNA for proinflammatory cytokines, and enhanced ability to stimulate naive T cells. Conversely, gal-1-DC induced rapid apoptosis of activated T cells. In vivo, gal-1-DC increased significantly the sensitization phase of contact hypersensitivity assays while inducing a drastic inhibition of the elicitation phase by triggering apoptosis of activated T cells in the dermis. Gal-1-DC represent a novel tool to control differentially the afferent and efferent arms of the T cell response.

Animals↗

PubMed2006

Regulated compartmentalization of programmed cell death-1 discriminates CD4+CD25+ resting regulatory T cells from activated T cells.

More effective discrimination between CD4+CD25+ regulatory T cells (Treg) and activated T cells would significantly improve the current level of purification of Treg and their therapeutic application. We observed that approximately 90% of Treg (positive for the nuclear transcription factor Forkhead winged helix protein-3 and able to inhibit naive T cell proliferation) isolated from the spleens or lymph nodes of normal mice did not express significant levels of the inhibitory receptor programmed cell death-1 (PD-1) on their surface, but retained PD-1 intracellularly. An identical phenotype was also identified for human CD4+CD25(high) T cells isolated from peripheral blood of healthy volunteers. By contrast, activated T cells expressed high levels of surface PD-1 that paralleled up-regulation of CD25 during effector cell expansion. This distinction allowed us to isolate CD4+CD25+PD-1(-) T cells with suppressive activity from mice immunized with mature allogeneic dendritic cells. Although purification was limited to resting Treg because TCR ligation induced up-regulation of surface PD-1, this strategy nevertheless represents a valuable step toward more definitive characterization of Treg and their improved purification for therapeutic assessment.

Amino Acid Sequence↗

PubMed2006

Ethanol affects the generation, cosignaling molecule expression, and function of plasmacytoid and myeloid dendritic cell subsets in vitro and in vivo.

The influence of ethanol (EtOH) on multiple dendritic cell (DC) subsets, in the steady state or following their mobilization in vivo, has not been characterized. Herein, generation of mouse bone marrow-derived DC (BMDC) in response to fms-like tyrosine kinase 3 ligand was inhibited by physiologically relevant concentrations of EtOH with selective suppression of plasmacytoid (p)DC. EtOH reduced surface expression of costimulatory molecules (CD40, CD80, CD86) but not that of coinhibitory CD274 (B7-H1) on resting or CpG-stimulated DC subsets. Interleukin (IL)-12p70 production by activated DC was impaired. Consistent with these findings, EtOH-exposed BMDC exhibited a reduced capacity to induce naïve, allogeneic T cell proliferation and impaired ability to prime T cells in vivo. DC subsets freshly isolated from EtOH-fed mice were also examined. Liver DC, inherently immature and resistant to maturation, exhibited little change in their low surface cosignaling molecule expression, whereas splenic DC showed reduced expression of surface costimulatory molecules in response to CpG stimulation in vivo. These splenic DC elicited reduced naïve, allogeneic T cell proliferation in vitro, and the stimulatory capacity of resting but not CpG-activated liver DC was reduced by chronic EtOH administration. T cells from animals primed with EtOH-exposed DC produced elevated levels of IL-10 following ex vivo challenge with donor alloantigen. Thus, EtOH impairs cytokine-driven differentiation and function of myeloid DC and pDC in vitro. Hepatic DC from chronic EtOH-fed mice are less affected than splenic DC, which exhibit impaired functional maturation following CpG stimulation. These results indicate a potential mechanism by which alcohol consumption is associated with immunosuppression.

Alcohol-Induced Disorders↗

PubMed2006

Renal transplantation reverses functional deficiencies in circulating dendritic cell subsets in chronic renal failure patients.

BACKGROUND: Dendritic cell (DC) subsets play critical roles in regulation of innate and adaptive immune responses. These important antigen-presenting cells have not been extensively analyzed in chronic renal failure (CRF), during dialysis, or before and after renal transplantation. METHODS: The incidence of circulating precursor (pre)-DC subsets relative to total peripheral blood mononuclear cells was analyzed in healthy controls, haemodialysis patients, peritoneal dialysis patients, CRF patients, and renal transplant (RT) recipients. DC subsets were identified and characterized phenotypically by multicolour flow cytometric analysis and purified by immunomagnetic bead isolation respectively. Cytokine production and circulating DC mobilizing cytokines were determined by ELISA. RESULTS: The incidence of circulating prePDC was reduced in all patients, but the incidence of circulating preMDC was comparable in RT and dialysis patients compared to healthy controls. CRF patients exhibited the lowest incidence of circulating preMDC and prePDC. Immunomagnetic bead-isolated preMDC and prePDC from haemodialysis patients were functionally impaired (reduced expression of surface costimulatory molecules and interleukin-12p70 production following bacterial lipopolysaccharide stimulation, and reduced interferon-alpha production following herpes simplex virus stimulation respectively, compared to healthy controls and RT recipients. Glomerular filtration rate correlated significantly with the incidence of circulating preMDC, but not prePDC. CONCLUSIONS: Deficiencies in the incidence and function of precursor DC can be reversed with successful renal transplantation achieving normal renal function. However, the finding of reduced incidence of circulating prePDC in the peripheral blood in RT recipients may be of significance in the pathogenesis of infections and malignancies.

Adult↗

PubMed2006

Heart allograft protection with low-dose carbon monoxide inhalation: effects on inflammatory mediators and alloreactive T-cell responses.

BACKGROUND: Carbon monoxide (CO), a byproduct of heme catalysis, has lately received considerable attention as a regulatory molecule in cellular and biological processes. CO has been shown to provide potent protection against a variety of tissue injuries. We hypothesized in this study that low concentration CO would be beneficial for organ allografts, which frequently undergo several types of injury such as ischemia/reperfusion, alloimmune reaction, and inflammation METHODS: The efficacy of low-dose CO was examined in a fully allogeneic LEW to BN rat heterotopic heart transplantation (HHTx) model. Recipients were kept in air or exposed to low-dose CO (20 ppm) for 14, 28, or 100 days after HHTx under short-course tacrolimus RESULTS: CO treatment (d0-28, 0-100) was remarkably effective in prolonging heart allograft survival to a median of >100 from 45 days in the air-control group, with significant reductions of arteritis, fibrosis, and cellular infiltration, including macrophages and T cells. CO inhibited intragraft upregulation of Th1 type cytokines (IL-2, IFNgamma), proinflammatory mediators (IL-1beta, TNFalpha, IL-6, COX-2), and adhesion molecule. Shorter CO exposure in early (0-13d) and late (14-28d) posttransplant periods also prolonged graft survival, with a significant inhibition of inflammatory mediators CONCLUSIONS: These results show that low dose CO inhalation protects heart allografts and can considerably prolong their survival. CO appears to function via multiple mechanisms, including direct inhibition of Th1 type cytokine production and regulation of inflammatory responses.

Administration, Inhalation↗

PubMed2006

Endotoxin modulates the capacity of CpG-activated liver myeloid DC to direct Th1-type responses.

DC are believed to play important roles in the induction and regulation of immune responses in the liver, an organ implicated in peripheral tolerance. Since the liver is located downstream of the gut, it is constantly exposed to bacterial LPS. Our recent observations indicate that prior exposure to endotoxin modulates subsequent liver DC responses to this TLR4 ligand. In this study, we demonstrate that endotoxin modifies the capacity of mouse liver myeloid DC (MDC) activated by CpG (TLR9 ligand) to direct Th1-type responses. IL-12 production by liver MDC was significantly lower than that of spleen MDC following CpG or Imiquimod (R837; TLR7 ligand) activation in vitro. In addition, allogeneic T cells stimulated by CpG-activated liver MDC secreted significantly lower levels of IFN-gamma than T cells stimulated with CpG-activated spleen MDC. A similar effect on liver DC was observed in response to in vivo CpG administration. This effect may be explained by exposure of the DC to endotoxin, because LPS attenuated IL-12 production by CpG-stimulated liver MDC, both in vitro and in vivo. Moreover, attenuation of the response to CpG was not observed in liver MDC from TLR4-mutant (C3H/HeJ) mice, in which TLR4 signaling is impaired. These data suggest that endotoxin-induced 'cross-tolerance' to TLR ligands in liver DC may contribute to down-regulation of hepatic immune responses.

Adjuvants, Immunologic↗

PubMed2006

Functional modification of CD11c+ liver dendritic cells during liver regeneration after partial hepatectomy in mice.

Local immunosuppression within the liver and sex steroid changes, in both blood and tissue during liver regeneration, are well-recognized events. Dendritic cells (DC) play pivotal roles in the induction and regulation of immune responses. Their numbers are expanded markedly in vivo by fms-like tyrosine kinase 3 ligand (Flt3L) administration, without modification of their maturation state. Recent evidence suggests that estrogen can modulate DC function and promote a Th2-type immune response. Few data are available concerning the role of DC in liver regeneration. After 75% partial hepatectomy (PH) in male C57BL/6 mice, CD11c+ liver (L)DC increased significantly within 6 hours and maintained an immature phenotype. Numbers returned to pre-hepatectomy levels by 24 hours. The expanded LDC population showed increased IL-10 and reduced IFN-gamma gene transcription. Using these DC compared with control LDC as T cell stimulators in 72-hour mixed leukocyte cultures, IL-10 production was enhanced and IFN-gamma production reduced. LDC isolated 6 hours after 75% PH exhibited enhanced estrogen receptor (ER) expression, concomitant with increased serum estrogen levels. By contrast, spleen (S)DC isolated before and after PH showed no significant changes in their function (maturation state, T cell stimulatory activity, cytokine production, and ER expression). Increased liver regeneration (more than 50%) was observed 48 hours after 40% PH in the Flt3L-pretreated compared with the PBS group. In conclusion, interstitial LDC may play a key role in local immune regulation during liver regeneration, possibly linking estrogen-mediated immune modulation and hepatocyte proliferation.

Animals↗

PubMed2006

Regulatory dendritic cell therapy in organ transplantation.

Dendritic cells (DCs) are uniquely well equipped antigen (Ag)-presenting cells. Their classic function was thought to be that of potent initiators of innate and adaptive immunity to infectious organisms and other Ags (including transplanted organs). Evidence has emerged, however, that DCs have a central and crucial role in determining the fate of immune responses toward either immunity or tolerance. This dichotomous function of DCs, coupled with their remarkable plasticity, renders them attractive therapeutic targets for immune modulation. In transplantation, much recent work has focused on the ability of DCs to silence immune reactivity in an Ag-specific manner in the hope of preventing rejection and diminishing reliance on potentially harmful immunosuppressive agents. Experimental strategies have included in vivo targeting of DCs, as well as ex vivo generation of regulatory (or tolerogenic) DCs with subsequent reinfusion (i.e. cell therapy). Different approaches to 'program' DC toward tolerogenic properties include genetic (transgene insertion), biologic (differential culture conditions, anti-inflammatory cytokine exposure) and pharmacologic manipulation. Recent data suggest a promising role for pharmacologic treatment as a means of generating potent regulatory DCs and have further stimulated speculation regarding their potential clinical application. Herein, we discuss evidence that the potential of regulatory DC therapy is considerable and that there are compelling reasons to evaluate it in the setting of organ transplantation in the near future.

Animals↗

PubMed2006

Dendritic cells as promoters of transplant tolerance.

Dendritic cells (DCs) play a crucial role during the initiation of immune responses against non-self antigens. Following organ transplantation, activated donor- and recipient-derived DCs participate actively in graft rejection by sensitising recipient T cells via the direct or indirect pathways of allorecognition, respectively. There is increasing evidence that immature/semi-mature DCs induce antigen-specific unresponsiveness or tolerance to self antigens, both in central lymphoid tissue and in the periphery, through a variety of mechanisms (deletion, anergy and regulation). In the past few years, DC-based therapy of experimental allograft rejection has focused on ex vivo biological, pharmacological and genetic engineering of DCs to mimic/enhance their natural tolerogenicity. Successful outcomes in rodent models have built the case that DC-based therapy may provide a novel approach to transplant tolerance. Ongoing research into the role that DCs play in the induction of tolerance should allow for its clinical application in the near future.

Animals↗

PubMed2005

CD4+ T cell responses elicited by different subsets of human skin migratory dendritic cells.

Skin dendritic cells (DC) are professional APC critical for initiation and control of adaptive immunity. In the present work we have analyzed the CD4+ T cell stimulatory function of different subsets of DC that migrate spontaneously from human skin explants, including CD1a+CD14- Langerhans' cells (LC), CD1a-CD14- dermal DC (DDC), and CD1a-CD14+ LC precursors. Skin migratory DC consisted of APC at different stages of maturation-activation that produced IL-10, TGF-beta1, IL-23p19, and IL-12p40, but did not release IL-12p70 even after exposure to DC1-driving stimuli. LC and DDC migrated as mature/activated APC able to stimulate allogeneic naive CD4+ T cells and to induce memory Th1 cells in the absence of IL-12p70. The potent CD4+ T cell stimulatory function of LC and DDC correlated with their high levels of expression of MHC class II, adhesion, and costimulatory molecules. The Th1-biasing function of LC and DDC depended on their ability to produce IL-23. By contrast, CD1a-CD14+ LC precursors migrated as immature-semimature APC and were weak stimulators of allogeneic naive CD4+ T cells. However, and opposite of a potential tolerogenic role of immature DC, the T cell allostimulatory and Th1-biasing function of CD14+ LC precursors increased significantly by augmenting their cell number, prolonging the time of interaction with responding T cells, or addition of recombinant human IL-23 in MLC. The data presented in this study provide insight into the function of the complex network of skin-resident DC that migrate out of the epidermis and dermis after cutaneous immunizations, pathogen infections, or allograft transplantation.

Antigen-Presenting Cells↗

PubMed2005

Dexamethasone preferentially suppresses plasmacytoid dendritic cell differentiation and enhances their apoptotic death.

Plasmacytoid dendritic cells (pDC) are an important source of type-1 interferon (IFN) following microbial infection and also play key roles in the induction of innate and adaptive immune responses. Here, we show that the glucocorticoid (GC) dexamethasone (Dex) strikingly reduces pDC (and myeloid DC) numbers in secondary lymphoid tissue and liver of normal and hematopoietic growth factor-mobilized mice and suppresses pDC differentiation from bone marrow precursors in vitro. Moreover, the apoptotic death of pDC in vitro was enhanced by exposure to Dex. Notably, however, Toll-like receptor 9 expression and virally induced IFNalpha production by residual pDC from Dex-treated animals were unaffected. Thus, whereas marked reduction in absolute numbers of pDC by GC may predispose to viral infection, often associated with GC-mediated immunosuppression, reductions in pDC and IFNalpha production may contribute to the beneficial effects on GC observed in systemic autoimmune disease, in which that both pDC and IFNalpha have been implicated.

Animals↗

PubMed2005

Hosts lacking fms-like tyrosine kinase 3 ligand exhibit marked reductions in transplant vascular sclerosis.

BACKGROUND: Mice lacking fms-like tyrosine kinase 3 ligand (Flt3L-/-) as the result of targeted gene disruption show severe reductions in dendritic cell (DC) subsets. We examined the development of vascular sclerosis and alloimmune reactivity in wild-type C57BL/6 (B6) and Flt3L-/- B6 (H2b) recipients of aortic allografts from normal BALB/c (H2d) donors. METHODS: DC deficiency was confirmed by flow cytometric analysis. Aortic allografts were anastomosed to the infrarenal portion of the recipient's abdominal aorta. No immunosuppressive therapy was administered. Transplant outcome was assessed 60 days postgrafting by histologic and immunohistochemical examination of the grafts. Host reactivity to donor alloantigens was determined by assaying splenic T-cell proliferation and T-cell infiltration within the grafts, immunoglobulin-G subclass alloantibody levels (by flow cytometry), and cytokine production (by enzyme-linked immunosorbent assay or graft immunohistochemistry). RESULTS: Sixty days posttransplant, BALB/c allografts in wild-type B6 recipients showed severe chronic arteriopathy (intimal thickening, alpha-smooth muscle actin+ cell proliferation, fibrosis, and elastic lamina disruption). In contrast, profound deficiency of host myeloid, "lymphoid-related," and pre-plasmacytoid DC subsets was accompanied by marked reductions in each feature of chronic rejection. Improvement in graft appearance was associated with antigen-specific suppression of ex vivo anti-donor T-cell proliferative activity and reductions in interferon-gamma but with enhancement of interleukin-10 secretion in response to donor alloantigen challenge. CONCLUSION: Permanent deficiency of host DC subsets resulting from targeted gene disruption markedly inhibits the development of transplant vascular sclerosis, associated with striking reductions in both anti-donor T-cell reactivity and immunoglobulin-G alloantibody production.

Animals↗

PubMed2005

Augmentation of type-1 polarizing ability of monocyte-derived dendritic cells from chronically immunosuppressed organ-transplant recipients.

BACKGROUND: Chronic immunosuppressive (IS) therapy impairs normal T-cell immune surveillance and may predispose to opportunistic infections and malignancies that represent life-threatening complication of solid-organ transplantation (SOTx). Our study was designed to ascertain the impact of chronic in vivo administration of IS on the ability of monocyte-derived dendritic cells (MoDC) to differentiate, mature, and function ex vivo. The potential of these cells to be implemented for DC-based adoptive immunotherapy was also considered. METHODS: MoDCs were propagated by conventional procedures, their phenotype was analyzed by flow cytometry, and their function was assessed by mixed leukocyte reaction, enzyme-linked immunoadsorbent assay, and ELISPOT assays. Nuclear translocation of nuclear factor (NF)-kB was analyzed by electrophoretic mobility shift assay. RESULTS: Circulating DC1s in peripheral blood were reduced in SOTx patients. MoDCs generated from patients displayed higher endocytic activity versus normal DCs, indicating their comparative immaturity. Patients' DCs exposed to pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin [IL]-1beta, and IL-6) were less able to mature, to stimulate recall antigen (Ag)- or allo-Ag-induced proliferation responses, or to secrete IL-12p70. These deficiencies were associated with a decrease in NF-kB translocation. In contrast, combination of pro-inflammatory cytokines and interferon (IFN)-gamma (a Th1-polarizing factor) augmented patients' DC1-type function and IL-12p70 production by way of an NF-kB-independent mechanism. CONCLUSIONS: Chronic IS restrains DC differentiation, maturation, and function at a transcriptional level; however, type-1 polarizing potential of patients' DC1 can be augmented ex vivo by a two-signal stimulation provided by pro-inflammatory cytokines and IFN-gamma. These results may have implications for DC-based immunotherapy of malignancies in the transplantation setting.

Active Transport, Cell Nucleus↗

PubMed2005

Low TLR4 expression by liver dendritic cells correlates with reduced capacity to activate allogeneic T cells in response to endotoxin.

Signaling via TLRs results in dendritic cell (DC) activation/maturation and plays a critical role in the outcome of primary immune responses. So far, no data exist concerning TLR expression by liver DC, generally regarded as less immunostimulatory than secondary lymphoid tissue DC. Because the liver lies directly downstream from the gut, it is constantly exposed to bacterial LPS, a TLR4 ligand. We examined TLR4 expression by freshly isolated, flow-sorted C57BL/10 mouse liver DC compared with spleen DC. Real-time PCR revealed that liver CD11c+CD8alpha- (myeloid) and CD11c+CD8alpha+ ("lymphoid-related") DC expressed lower TLR4 mRNA compared with their splenic counterparts. Lower TLR4 expression correlated with reduced capacity of LPS (10 ng/ml) but not anti-CD40-stimulated liver DC to induce naive allogeneic (C3H/HeJ) T cell proliferation. By contrast to LPS-stimulated splenic DC, these LPS-activated hepatic DC induced alloantigen-specific T cell hyporesponsiveness in vitro, correlated with deficient Th1 (IFN-gamma) and Th2 (IL-4) responses. When higher LPS concentrations (> or =100 ng/ml) were tested, the capacity of liver DC to induce proliferation of T cells and Th1-type responses was enhanced, but remained inferior to that of splenic DC. Hepatic DC activated by LPS in vivo were inferior allogeneic T cell stimulators compared with splenic DC, whereas adoptive transfer of LPS-stimulated (10 ng/ml) liver DC induced skewing toward Th2 responses. These data suggest that comparatively low expression of TLR4 by liver DC may limit their response to specific ligands, resulting in reduced or altered activation of hepatic adaptive immune responses.

Animals↗

PubMed2005

Comparative analysis of the fate of donor dendritic cells and B cells and their influence on alloreactive T cell responses under tacrolimus immunosuppression.

We have shown that tacrolimus (TAC)-induced liver allograft acceptance is associated with migration and persistence of donor B cells and dendritic cells (DC). To clarify whether these MHC class II+ leukocytes have favorable roles in inducing tolerance, we analyzed recipient T cell reactions after allogeneic B or DC infusion. LEW rat B cells localized exclusively in BN host B cell follicles without any direct contact with host T cells. While few donor DC migrated to T cell areas and marginal zones, they were captured by host APC, suggesting that allogeneic MHC class II+ cells may induce immune reactions via the indirect pathway. Although DC-infused non-immunosuppressed recipients showed enhanced ex vivo anti-donor responses, persistent in vitro donor-specific hyporeactivity was seen equally with donor DC or B cell infusion under TAC. The results indicate that donor MHC class II+ APC are capable of regulating recipient immune reactions under TAC. Possible involvement of the indirect pathway of allorecognition is discussed.

Animals↗

PubMed2005

Organ transplantation--how much of the promise has been realized?

Since the introduction of organ transplantation into medical practice, progress and optimism have been abundant. Improvements in immunosuppressive drugs and ancillary care have led to outstanding short-term (1--3-year) patient and graft survival rates. This success is mitigated by several problems, including poor long-term (>5-year) graft survival rates, the need for continual immunosuppressive medication and the discrepancy between the demand for organs and the supply. Developing methods to induce transplant tolerance, as a means to improve graft outcomes and eliminate the requirement for immunosuppression, and expanding the pool of organs for transplantation are the major challenges of the field.

Animals↗

PubMed2005

Rapamycin-treated, alloantigen-pulsed host dendritic cells induce ag-specific T cell regulation and prolong graft survival.

Tolerogenic properties of dendritic cells (DC), particularly those in the immature state, and their therapeutic potential are increasingly being recognized. Among several distinct approaches to generate stably immature DC, pharmacologic manipulation stands out as a promising and clinically applicable option. We have shown recently that the immunophilin ligand rapamycin (Rapa) can inhibit DC maturation and their effector functions. Here, we examined the impact of Rapa exposure on subsequent alloantigen (Ag) presentation by myeloid DC via the indirect pathway. Rapa-treated, allogeneic lysate-pulsed host DC (Rapa-DC) were inferior stimulators of syngeneic T cells, compared to lysate-pulsed control DC. Rapa exposure did not block alloAg uptake by DC nor impair their in vivo homing to splenic T cell areas after adoptive transfer. T cells primed by Rapa-treated, alloAg-pulsed DC showed decreased capacity to produce IL-2 and IFNgamma, and were hyporesponsive to subsequent challenge via both the direct and indirect pathways, in an Ag-specific manner. When infused 1 week before transplantation, these Rapa-DC significantly prolonged alloAg-specific heart graft survival. This effect was reversed by systemic IL-2 administration but enhanced by either repeated infusion of the cells or a short post-transplant course of FK506. These therapeutic effects, achieved by targeting both major pathways of allorecognition, provide the basis for a clinically applicable strategy to suppress graft rejection.

Adoptive Transfer↗