Pediatric "pet consort dermatitis"-Allergic contact dermatitis from transfer of bronopol from a pet cat.

Consort dermatitis refers to an allergic contact dermatitis caused by transfer from an intimate contact to a sensitized patient. Although close contact with other humans most commonly provokes consort dermatitis, pets have been the source in a minority of cases. We present a unique case of transfer dermatitis from a patient's cat litter to her forearms. Pediatric dermatologists should be aware of the possibility of consort or "transfer" allergic contact dermatitis from pets.

Development and Evaluation of Biodegradable Particles Coloaded With Antigen and the Toll-Like Receptor Agonist, Pentaerythritol Lipid A, as a Cancer Vaccine.

Immune adjuvants are important components of current and prospective cancer vaccines. In this study, we aimed at evaluating the use of a synthetic lipid A derivative, pentaerythritol lipid A (PET lipid A), loaded into poly(lactic-co-glycolic acid) particles, as a potential cancer vaccine adjuvant. Poly(lactic-co-glycolic acid) particles (size range: 250-600 nm) were successfully formulated to include PET lipid A and/or the model tumor antigen, chicken ovalbumin (OVA). It was shown that particulated PET lipid A had a distinct advantage at promoting secretion of the immune potentiating cytokine, IL-12p70, and upregulating key costimulatory surface proteins, CD86 and CD40, in murine dendritic cells in vitro. In a murine tumor model, involving prophylactic vaccination with various permutations of soluble versus particulated formulations of OVA with or without PET lipid A, modest benefit was observed in terms of OVA-specific cell-mediated immune responses when PET lipid A was delivered in particles. These findings translated into a corresponding trend toward increased survival of mice challenged with OVA-expressing tumor cells (E.G7). In terms of translation of safe adjuvants into the clinic, these results promote the concept of delivering toll-like receptor-4 agonists in particles because doing so improves their adjuvant properties, while decreasing the chances of adverse effects due to off-target uptake by nonphagocytic cells.

Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis.

OBJECTIVE: To evaluate immune responses in fingolimod-treated patients with multiple sclerosis (MS) against influenza vaccine (to test for responses against anticipated novel antigens in seronegative patients) and recall (tetanus toxoid [TT] booster dose) antigens. METHODS: This was a blinded, randomized, multicenter, placebo-controlled study. Patients aged 18 to 55 years with relapsing MS were randomized (2:1) to fingolimod 0.5 mg or placebo for 12 weeks. At week 6, patients received seasonal influenza vaccine (containing antigens of California, Perth, and Brisbane virus strains) and TT booster dose. Antibody titers against influenza and TT were estimated at baseline (prevaccination) and 3 and 6 weeks postvaccination. The primary efficacy variable was responder rate (proportion of patients showing seroconversion or significant increase [≥4-fold] in antibody titers against at least one influenza virus strain) at 3 weeks postvaccination and vs placebo. RESULTS: Of 138 randomized patients (fingolimod 95, placebo 43), 136 completed the study (2 discontinued in fingolimod group). The responder rates (odds ratio; 95% confidence interval) for influenza vaccine (fingolimod vs placebo) were 54% vs 85% (0.21; 0.08-0.54) at 3 weeks and 43% vs 75% (0.25; 0.11-0.57) at 6 weeks postvaccination. For TT, responder rates were 40% vs 61% (0.43; 0.20-0.92) at 3 weeks and 38% vs 49% (0.62; 0.29-1.33) at 6 weeks postvaccination. Adverse events were reported in 86.3% and 79.1% of patients receiving fingolimod and placebo, respectively. CONCLUSION: Most fingolimod-treated patients with MS were able to mount immune responses against novel and recall antigens and the majority met regulatory criteria indicating seroprotection. However, response rates were reduced compared with placebo-treated patients. This should be kept in mind when vaccinating patients on fingolimod. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in some patients with MS receiving immunizations, concurrent fingolimod treatment in comparison to placebo decreases vaccination-induced immune responses.

FTY720 does not protect from traumatic brain injury in mice despite reducing posttraumatic inflammation.

Inflammation is a pathological hallmark of traumatic brain injury (TBI). Recent evidence suggests that immune cells such as lymphocytes are of particular relevance for lesion development after TBI. FTY720, a sphingosine-1-phosphate (S1P) receptor modulator, sequesters T lymphocytes in lymphoid organs and has been shown to improve outcome in a variety of neurological disease models. We investigated the mode of FTY720 action in models of TBI. Focal cortical cryolesion was induced in C57BL/6 mice treated with FTY720 (1mg/kg) or vehicle immediately before injury. Lesion size was assessed 24h later. Immune cells in the blood and brain were counted by flow cytometry and immunocytochemistry. The integrity of the blood-brain barrier was analyzed using Evans Blue dye. To validate the findings in a diffuse brain trauma model, FTY720-treated mice and controls were subjected to weight drop contusion injury and neurological deficits were assessed until day 7. As expected FTY720 significantly lowered the numbers of circulating lymphocytes and attenuated the invasion of immune cells into the damaged brain parenchyma. However, FTY720 was unable to improve lesion size or functional outcome in both trauma models at either stage, i.e. acute vs chronic. Accordingly, the extent of blood-brain barrier disruption and neuronal apoptosis was similar between FTY720-treated mice and controls. We conclude that pharmacological S1P receptor modulation is an unfavorable strategy to combat TBI. Moreover, our findings put into perspective the pathophysiological relevance of inflammatory cells in traumatic neurodegeneration.

Cutaneous delayed-type hypersensitivity in patients with atopic dermatitis: reactivity to topical preservatives.

BACKGROUND: Patients with atopic dermatitis (AD) have chronic dry skin to which they frequently apply skin care products containing preservatives, and they are predisposed to developing cutaneous delayed-type hypersensitivity. OBJECTIVE: We sought to compare the rates of positive patch test reactions to allergens on the North American Contact Dermatitis Group (NACDG) standard tray among patients with and without AD and to assess whether atopic patients in our database were more likely to patch test positive to preservatives. METHODS: A total of 2453 patients underwent patch testing to the NACDG standard screening series. The incidence of positive patch test reaction among patients with AD (n = 342) and without AD (n = 2111) was assessed. Statistical analysis was done using a χ(2) test. RESULTS: Compared with nonatopic patients, patients with AD were statistically more likely to have positive patch tests. AD was associated with contact hypersensitivity to quaternium-15, imidazolidinyl urea, DMDM hydantoin, and 2-bromo-2-nitropropane-1,3-diol but not to parabens, formaldehyde, or diazolidinyl urea. LIMITATIONS: Only patients suspected of having allergic contact dermatitis were tested. Our population was geographically limited to metropolitan Kansas City, MO, and metropolitan New York City, NY. CONCLUSIONS: Patients with AD should avoid the use of skin care products preserved with formaldehyde releasers.

Efficiency of pH-sensitive fusogenic polymer-modified liposomes as a vaccine carrier.

The usefulness of pH-sensitive fusogenic polymer-(succinylated poly(glycidol)-(SucPG-) modified liposomes as a vaccine carrier in the induction of immune responses was evaluated. Mice were intraperitoneally immunized with ovalbumin- (OVA-) containing SucPG-modified liposomes. After immunization, significant OVA-specific antibodies were detected in the serum. When sera were analyzed for isotype distribution, OVA-specific IgG1 antibody responses were noted in mice immunized with OVA-containing polymer-unmodified liposomes, whereas immunization with OVA-containing SucPG-modified liposomes resulted in the induction of OVA-specific IgG1, IgG2a, and IgG3 Ab responses. In spleen lymphocytes from mice immunized with OVA-containing SucPG-modified liposomes, both IFN-γ-(Th1-type-) and IL-4-(Th2 type-) specific mRNA were detected. Moreover, substantial production of IFN-γ and IL-4 was demonstrated in spleen cells from OVA-containing SucPG-modified liposomes in vitro. These results suggest that the pH-sensitive fusogenic polymer-(SucPG-) modified liposomes would serve effectively as an antigen delivery vehicle for inducing Th1 and Th2 immune responses.

Effect of sphingosine 1-phosphate (S1P) receptor agonists FTY720 and CYM5442 on atherosclerosis development in LDL receptor deficient (LDL-R⁻/⁻) mice.

OBJECTIVES: Sphingosine 1-phosphate (S1P)--a lysosphingolipid present in HDL--exerts atheroprotective effects in vitro, while FTY720, a non-selective S1P mimetic inhibits atherosclerosis in LDL receptor-deficient (LDL-R⁻/⁻) mice under conditions of severe hypercholesterolemia. We here examined the effect of FTY720 and a selective S1P receptor type 1 agonist CYM5442 on atherosclerosis in moderately hypercholesterolemic LDL-R⁻/⁻ mice. METHODS AND RESULTS: LDL-R⁻/⁻ mice fed Western diet (0.25% cholesterol) were given FTY720 (0.4 mg/kg/day) or CYM5442 (2.0 mg/kg/day) for 18 weeks. FTY720 but not CYM5422 persistently lowered blood lymphocytes, depleted CD4⁺ and CD8⁺ T cells in spleen and lymph nodes, and reduced splenocyte IL-2 secretion. However, both compounds reduced the activity of splenic and peritoneal macrophages as inferred from the down-regulated CD68 and MHC-II expression in CD11b⁺ cells and the reduced IL-6 secretion in response to LPS, respectively. CYM5442 and FTY720 reduced weight gain, white adipose tissue depots and fasting glucose suggesting improvement of metabolic control, but failed to influence atherosclerosis in LDL-R⁻/⁻ mice. CONCLUSION: Despite down-regulating macrophage function and--in case of FTY720--altering lymphocyte distribution CYM5442 and FTY720 fail to affect atherosclerosis in moderately hypercholesterolemic LDL-R⁻/⁻ mice. We hypothesize that S1P mimetics exert atheroprotective effects only under conditions of increased cholesterol burden exacerbating vascular inflammation.

Fingolimod in multiple sclerosis: mechanisms of action and clinical efficacy.

Fingolimod, also known as FTY720, has recently been approved by the regulatory authorities in the US, EU, Australia, Russia, among others, for the treatment of relapsing-remitting multiple sclerosis. Fingolimod therefore represents the first oral drug for the treatment of this autoimmune disease of the central nervous system. Fingolimod modulates sphingosine-1 phosphate receptors and has unique immunoregulatory properties. Mechanistic studies from animal models have shown that fingolimod prevents immune cells from exiting from the lymphoid tissue and reaching the inflammatory tissue. Indeed, two phase III studies that laid the basis for fingolimod's approval demonstrated that fingolimod efficiently improves the relapse rate compared to both placebo and one of the standard MS medications. In this review, we will summarize the immunological profile of fingolimod, discuss the possible direct neurobiological effects that have been suggested recently and present the clinical data regarding the efficacy and safety profiles of this promising new drug.

A mechanistically novel, first oral therapy for multiple sclerosis: the development of fingolimod (FTY720, Gilenya).

Multiple sclerosis (MS) is a chronic autoimmune disorder affecting the central nervous system (CNS) through demyelination and neurodegeneration. Until recently, major therapeutic treatments have relied on agents requiring injection delivery. In September 2010, fingolimod/FTY720 (Gilenya, Novartis) was approved by the FDA as the first oral treatment for relapsing forms of MS. Fingolimod is a novel compound produced by chemical modification of a fungal precursor. Its active metabolite, formed by in vivo phosphorylation, modulates sphingosine 1-phosphate (S1P) receptors that are a subset of a larger family of cell-surface, G protein-coupled receptors (GPCRs) mediating the effects of bioactive lipids known as lysophospholipids. Fingolimod's mechanism of action in MS is not completely understood; however, its relevant biology indicates a fundamentally different mechanism compared to all previously approved MS therapies, with evolving research supporting both immunological and nervous system activities. This duality may herald a paradigm shift in the treatment of MS and other neurological disorders.

Pig embryonic pancreatic tissue as a source for transplantation in diabetes: transient treatment with anti-LFA1, anti-CD48, and FTY720 enables long-term graft maintenance in mice with only mild ongoing immunosuppression.

OBJECTIVE: Defining an optimal costimulatory blockade-based immune suppression protocol enabling engraftment and functional development of E42 pig embryonic pancreatic tissue in mice. RESEARCH DESIGN AND METHODS: Considering that anti-CD40L was found to be thrombotic in humans, we sought to test alternative costimulatory blockade agents already in clinical use, including CTLA4-Ig, anti-LFA1, and anti-CD48. These agents were tested in conjunction with T-cell debulking by anti-CD4 and anti-CD8 antibodies or with conventional immunosuppressive drugs. Engraftment and functional development of E42 pig pancreatic tissue was monitored by immunohistology and by measuring pig insulin blood levels. RESULTS: Fetal pig pancreatic tissue harvested at E42, or even as early as at E28, was fiercely rejected in C57BL/6 mice and in Lewis rats. A novel immune suppression comprising anti-LFA1, anti-CD48, and FTY720 afforded optimal growth and functional development. Cessation of treatment with anti-LFA1 and anti-CD48 at 3 months posttransplant did not lead to graft rejection, and graft maintenance could be achieved for >8 months with twice-weekly low-dose FTY720 treatment. These grafts exhibited normal morphology and were functional, as revealed by the high pig insulin blood levels in the transplanted mice and by the ability of the recipients to resist alloxan induced diabetes. CONCLUSIONS: This novel protocol, comprising agents that simulate those approved for clinical use, offer an attractive approach for embryonic xenogeneic transplantation. Further studies in nonhuman primates are warranted.

FTY720 (fingolimod) for relapsing multiple sclerosis.

FTY720 (fingolimod) is a structural analogue of sphingosine, an endogenous lysophospholipid, which targets sphingosine-1-phosphate receptors after biotransformation to FTY720-phosphate. The immunomodulatory properties of this agent are mainly related to its ability to entrap lymphocytes in secondary lymphoid organs, reducing their availability for cell-mediated immune responses. Emerging evidence suggests that FTY720 also exerts direct actions on glial and precursor cells of the CNS which may be relevant for the process of tissue repair after injury. The therapeutic effects of the drug observed in animal models of human multiple sclerosis have provided the experimental basis for its clinical application. A recent Phase II study has demonstrated that oral FTY720 is effective in reducing disease activity in relapsing multiple sclerosis with a favorable adverse-effect profile. These results are awaiting confirmation in the three ongoing Phase III clinical trials evaluating FTY720 for relapsing-remitting multiple sclerosis.

Studies on toxic oil syndrome: development of an enzyme-linked immunosorbent assay for 3-(N-phenylamino)propane-1,2-diol in human urine.

The fatty acid esters of 3-(N-phenylamino)propane-1,2-diol (PAP) are biomarkers of toxic oil batches that caused toxic oil syndrome (TOS), an intoxication that caused over 400 deaths and affected 20,000 people in Spain in 1981. PAP esters are converted into PAP by human pancreatic lipase. The in vivo biotransformation of PAP in two mouse strains generated potentially toxic metabolites. Here we report an enzyme-linked immunosorbent assay (ELISA) for PAP detection incorporating antibodies generated using PAP-hapten derivatives 1 and 2. The immunizing haptens were designed to recognize the phenylamino and hydroxymethylene moieties of the PAP structure. The antisera raised against 1-HCH showed greater affinity for free PAP, as demonstrated in competitive experiments using either 1-BSA or 2-BSA as coating antigens. The developed ELISA detects PAP at a threshold of 130 µg L(-1) and can be used over a wide range of pH and ionic strength values. The assay can be applied to human urine samples, after a simple treatment method, with good recovery according to the correlation obtained when analyzing blind spiked urine samples.

Fingolimod: a novel immunosuppressant for multiple sclerosis.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of fingolimod, a novel immune modulator. DATA SOURCES: Information was obtained through a MEDLINE search (1966-February 2007) and from published abstracts. Search terms included fingolimod, FTY720, FTY-720, and sphingosine-1-phosphate receptor agonist. STUDY SELECTION AND DATA EXTRACTION: All English-language studies and abstracts pertaining to fingolimod were considered for inclusion. Preference was given to human data. DATA SYNTHESIS: Fingolimod is the first in a new class of immune modulators known as the sphingosine-1-phosphate receptor agonists. It is administered orally once daily and causes a dose-related reduction in the number of circulating lymphocytes by preventing their egress from secondary lymph organs, but it does not alter T-cell activation or proliferation. Bradycardia and lymphopenia are the most common adverse effects. Clinical trials have evaluated the efficacy of fingolimod in renal transplantation and multiple sclerosis (MS). Further research for renal transplantation will not take place, but Phase 3 studies in MS are underway, as Phase 2 study results are favorable. CONCLUSIONS: Due to its distinct mechanism of action and its oral administration, fingolimod may be a useful therapeutic option for patients with relapsing forms of MS. More data are needed to assess the safety and clinical utility of fingolimod.

Current perspectives on FTY720.

The search for effective immunosuppressants with fewer side effects continues not only for transplantation, but also for autoimmune diseases. With a novel mechanism of action (sphingosine-1 receptor modulation), oral FTY720 (fingolimod) has the potential to address this need. FTY720 has been preclinically tested with promising results in transplantation and autoimmune disease models. Phase I studies explored the pharmacokinetics and pharmacodynamics of this novel therapeutic concept. Recently, the surprising results of two sister Phase III studies in de novo renal transplant patients, as well as a Phase II study in patients with relapsing multiple sclerosis, were published. This review discusses these findings as well as their implications for the future of sphingosine-1 receptor modulation.

The S1P-analog FTY720 differentially modulates T-cell homing via HEV: T-cell-expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer patches.

Sphingosine-1-phosphate (S1P) and its receptor S1P1 control T-cell egress from thymus and secondary lymphoid organs (SLOs). To further define the role of S1P1 in lymphocyte trafficking, we performed adoptive transfer experiments and intravital microscopy (IVM) using both S1P1-/- lymphocytes and recipient wild-type (WT) mice treated with FTY720, an immunosuppressant that downmodulates S1P receptors. S1P1 deficiency and FTY720 caused rapid disappearance of T cells from blood, prolonged retention in SLOs, and accumulation in bone marrow, but did not alter interstitial T-cell motility in peripheral lymph nodes (PLNs) as assessed by multiphoton IVM. However, S1P1-/- lymphocytes displayed reduced short-term homing to PLNs due to attenuated integrin-mediated firm arrest in high endothelial venules (HEVs). By contrast, S1P1-/- T cells homed normally to Peyer patches (PPs), whereas S1P1-/- B cells had a marked defect in homing to PPs and arrested poorly in PP HEVs. Therefore, S1P1 not only controls lymphocyte egress from SLOs, but also facilitates in a tissue- and subset-specific fashion integrin activation during homing. Interestingly, FTY720 treatment enhanced accumulation of both S1P1 sufficient and S1P1-/- T cells in PPs by enhancing integrin-mediated arrest in HEVs. Thus, FTY720 exerts unique effects on T-cell traffic in PPs that are independent of T-cell-expressed S1P1.

Preoperative administration of FTY720 prolonged renal allograft survival.

BACKGROUND: FTY729 is an immunomodulator obtained by chemical modification of Myriocin(ISI-1) which exists in the culture filtrate of an ascomycete, Isaria sinclairii. It has been reported that postoperative administration of FTY720 prolonged survival of various kinds of transplanted organs. In the present study, we evaluated the effect of 2-day preoperative administration of FTY 720 on graft survival. MATERIALS AND METHODS: We used a rat renal transplantation model in which Wistar King Aptekman Hokkaido (WKAH, RT1K) served as the organ donor and Lewis (LEW, RTl) as the recipient. FTY720 was given to the recipients consecutively 2 days (day-2, day-1) before transplantation at the doses of 1, 3 or 5 mg/kg/day. Renal allograft survivals, hematological parameters of recipient blood and phenotypic analysis of recipient splenic cells and graft infiltrate were evaluated. RESULTS: Consecutive 2-day preoperative oral administration of FTY 720 at the doses of 1, 3 or 5 mg/kg/day significantly prolonged WKAH allograft survivals compared with those of the untreated recipients. The number of peripheral blood lymphocytes was markedly decreased in the recipients treated with FTY720 at the doses of 3 mg/kg/day or 5 mg/kg/day on the 5th postoperative day. Preoperative FTY 720 administration significantly decreased the number of CD4 positive cells and the percentage of interleukin 2 receptor (IL-2 R) positive cells infiltrating both spleen and allograft at the dose of 3 mg/kg/day or 5 mg/kg/day. CONCLUSION: FTY 720 could act as a safe and potent immunomodulator by decreasing the number of peripheral lymphocytes, especially CD4 positive cells and IL-2R positive cells when it is given to the recipient preoperatively.

FTY720 prolongs clear corneal allograft survival with a differential effect on different lymphocyte populations.

BACKGROUND: FTY720 is a potent immunomodulator with unique effects on lymphocyte homing and has recently proved to be safe and effective in renal transplantation in man. The authors investigated the potency of FTY720 in inhibiting allograft rejection in the rat model of orthotopic allogeneic penetrating keratoplasty. METHODS: Penetrating keratoplasties were performed using Fisher rats as donors and Lewis rats as recipients or donors: group 1 (n = 10), allogeneic control; group 2 (n = 10), Lewis/Lewis syngeneic control; group 3 (n = 9), mycophenolate mofetile (MMF) 40 mg/kg; group 4 (n = 10), FTY720 1.2 mg/kg; group 5 (n = 8), FTY720 0.3 mg/kg. Four animals from each group were sacrificed for immunohistological evaluation on day 14. Medication in the therapy groups was given for 18 days. RESULTS: The mean (SD) rejection free graft survival time was 11.3 (0.8) days for the allogeneic control (group 1), 24.6 (2.5) days for group 3 (MMF), 44.5 (5.7) days for group 4 (FTY720 1.2 mg/kg), and 35.3 (5.7) days for group 5 (FTY720 0.3 mg/kg) (p<0.05). The allogeneic control showed a dense infiltration with CD4+, CD8+, CD161+ (NK-cells), CD25+ (IL2 receptor), and macrophages. In the therapy groups the density of infiltrating CD4+, CD8+, CD161+ (NK-cells), and CD25+ (IL2 receptor) cells was notably reduced compared with the allogeneic control (p<0.05). In group 5 however, the reduction of infiltration by CD4+ cells was higher than the reduction of infiltration by CD8+ (p<0.05) and CD161+ (NK) cells. DISCUSSION: Oral immunosuppression with FTY720 significantly prolongs corneal allograft survival in this transplant model. The results suggest that FTY720 has a different effect on certain lymphocyte populations. CD4+ cells seem to be more affected than CD8+ cells and NK-cells.

New paradigms in immunosuppression.

With the decrease in donor quality and the increase in recipient co-morbidities, transplantation immunosuppression is changing. New paradigms in transplantation include co-stimulation, lymphocyte retrafficking, and inhibiting antibody production. With these new paradigms come new immunosuppressive agents. While these new agents show great promise, their use in day-to-day clinical transplantation remains to be seen.

Mechanisms of idiosyncratic drug reactions: the case of felbamate.

Idiosyncratic drug reactions (IDR) are a specific type of drug toxicity characterized by their delayed onset, low incidence and reactive metabolite formation with little, if any, correlation between pharmacokinetics or pharmacodynamics and the toxicological outcome. As the name implies, IDR are unpredictable and often result in the post marketing failure of otherwise useful therapies. Examples of drugs, which have failed as a result of IDR in recent years, include trovafloxacin, zileuton, troglitazone, tolcapone and felbamate. To date there exists no pre-clinical model to predict these adverse drug reactions and a mechanistic understanding of these toxicities remains limited. In an attempt to better understand this class of drug toxicities and gain mechanistic insight, we have studied the IDR associated with a model compound, felbamate. Our studies with felbamate are consistent with the theory that compounds which cause IDR undergo bioactivation to a highly reactive electrophilic metabolite that is capable of forming covalent protein adducts in vivo. In additon, our data suggest that under normal physiological conditions glutathione plays a protective role in preventing IDR during felbamate therapy, further emphasizing a correlation between reactive metabolite formation and a toxic outcome. Clinical studies with felbamate have been able to demonstrate an association between reactive metabolite formation and a clinically relevant toxicity; however, additional research is required to more fully understand the link between reactive metabolite formation and the events which elicit toxicity. Going forward, it seems reasonable that screening for reactive metabolite formation in early drug discovery may be an important tool in eliminating the post-marketing failure of otherwise useful therapies.

CC chemokine receptor 7-dependent and -independent pathways for lymphocyte homing: modulation by FTY720.

Cognate interaction of chemokine receptor CCR7 on lymphocytes with its ligands CCL19 and CCL21 expressed on high endothelial venules (HEVs) is essential for effective migration of T and B cells across HEVs into secondary lymphoid organs. Plt mice, which lack expression of CCL19 and CCL21-ser, both ligands for CCR7 on HEVs, as well as CCR7-deficient mice, have a defective cell migration and reduced homing of lymphocytes. FTY720, a novel immunosuppressant, causes a reduction of lymphocytes in peripheral blood and tissues and their sequestration into lymphoid tissues. In this study we demonstrate that FTY720 rescues the homing defect in both CCR7(-/-) mice and plt mice. After FTY720 treatment, the number of CD4(+) and CD8(+) T cells as well as B cells in peripheral blood is reduced while pertussis toxin-sensitive homing into peripheral lymph nodes, mesenteric lymph node, and Peyer's patches is increased. Immunohistology demonstrates that FTY720 enables these cells to enter lymphoid tissue through HEVs. Thus, our data suggest an alternative G-alpha(i)-dependent, CCR7-CCL19/CCL21-independent mechanism for lymphocyte homing through HEVs which is strongly augmented in the presence of FTY720.