Immunomodulatory Agents (immunomodulatory + agent)

Distribution by Scientific Domains
Distribution within Medical Sciences

Selected Abstracts

Transient T,cell accumulation in lymph nodes and sustained lymphopenia in mice treated with FTY720

Abstract FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) is an orally available immunomodulatory agent that induces severe peripheral blood lymphopenia. Most studies of these lymphopenic effects have been limited to short-term exposure to FTY720. FTY720 alters the ability of lymphocytes to respond to sphingosine-1-phosphate (S1P) through S1P receptors, particularly S1P1. FTY720 affects different leukocyte populations and their trafficking through major lymphoid organs. We show the dynamics of CD4,T, CD8,T, and B,lymphocyte recirculation in all major lymphoid compartments during 21-day FTY720 treatment of normal C57BL/6 mice. Following a transient increase in peripheral lymph nodes and Peyer's patches, lymphocyte recirculation reaches a new steady state. Other lymphoid organs show transient changes in lymphocyte composition with various patterns. At 21,days of FTY720 treatment, total body lymphocyte content is reduced by 20% and blood lymphocytes by 80%. Modeling suggests that the new steady state is due to a combination of reduced naive lymphocyte release from the thymus and a transient reduction of lymphocyte egress from lymph nodes. Our data indicate that the commonly held belief that FTY720 blocks lymphocyte egress from lymph nodes cannot fully explain the lymphocyte dynamics observed with prolonged treatment. [source]

Eruption cyst formation associated with cyclosporin A

A case report
Abstract Background: Cyclosporin A (CyA) is a potent immunomodulatory agent with a wide range of applications. Despite its therapeutic value, multiple adverse effects of CyA have been identified. This case report describes eruption cyst formation as a possible adverse effect of CyA administration during tooth eruption in a boy treated with CyA as a consequence of a cardiac transplantation. The clinical diagnosis of eruption cyst was confirmed by histopathological examination. Treatment: The periodontal treatment consisted of supragingival and subgingival scaling, followed by surgical removal of the tissues overlying the crowns of the teeth associated with eruption cysts, and flap surgery in the region of gingival overgrowth. The patient was then placed on quarterly periodontal supportive therapy and his immunosuppressive medication was switched from CyA to tacrolimus. Results: Twenty months after therapy, neither new cyst formation nor recurrence of gingival overgrowth was registered. Conclusion: Formation of an eruption cyst may be an adverse effect of CyA in children with erupting teeth. Zusammenfassung Hintergrund: Cyclosporin A (CyA) ist potentes immunmodulierendes Pharmakon mit einer breiten Applikationsmöglichkeit. Unabhängig von seinem therapeutischen Wert sind multiple Nebeneffekte von CyA beschrieben worden. Dieser Fallbericht beschreibt die Bildung einer Zyste beim Zahndurchbruch als eine mögliche Nebenwirkung von CyA Medikation bei einem Jungen, der mit CyA wegen einer Herztransplantation behandelt wurde. Die klinische Diagnose der Zystenbildung wurde histopathologisch bestätigt. Behandlung: Die parodontale Behandlung bestand in supragingivaler und subgingivaler Zahnreinigung gefolgt von der chirurgischen Entfernung des die Zahnkronen überdeckenden Gewebes, was mit der Zystenbildung verbunden war, und der Lappenchirurgie in der Region der gingivalen Wucherung. Der Patient wurde dann in das vierteljährliche parodontale Recall übernommen, und seine immunsuppressive Medikation wurde von CyA zu Tacrolimus verändert. Ergebnisse: 20 Monate nach der Therapie wurde weder eine neue Zystenbildung noch eine Wiederkehr der gingivalen Wucherung registriert. Schlussfolgerung: Die Bildung einer Durchbruchszyste kann eine Nebenwirkung bei der CyA Medikation bei Kindern während des Zahndurchbruchs sein. Résumé La cyclosporine A (CyA) est un agent immuno-modulateur puissant avec un large éventail d'applications. Malgré sa valeur thérapeutique, de multiples effets secondaires CyA ont été identifiés. Ce rapport de cas décrit une formation de kystes d'éruption qui pourrait être un effet secondaire possible de l'administration de CyA durant l'éruption dentaire chez un garçon traité par CyA à la suite d'une transplantation cardiaque. Le diagnostic clinique du kyste d'éruption a été confirmé par l'histopathologie. Le traitement parodontal a consisté en détartrage et surfaçage suivis par l'enlèvement chirurgical des tissus recouvrant les couronnes des dents associés aux kystes d'éruptions, et une chirurgie par lambeaux dans la région d'accroissement gingivale. L'enfant a bénéficié d'un suivi parodontal trimestriel et sa médication immunosuppressive est passée du CyA au tacrolimus. Vingt mois après le traitement, ni la formation de kystes ni la réapparition d'hypertrophie gingivale n'a été enregistrée. La formation de kystes d'éruption pourrait donc être un effet secondaire de l'utilisation de la CyA chez les enfants au moment de l'éruption des dents. [source]

Synergistic antitumor effects of lenalidomide and rituximab on mantle cell lymphoma in vitro and in vivo,

Liang Zhang
Rituximab (RTX), a chimeric anti-CD20 antibody, is associated with direct induction of apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) with clinical efficacy in mantle cell lymphoma (MCL). Lenalidomide (LEN), a novel immunomodulatory agent, sensitizes tumor cells and enhances ADCC. Our study attempted to elucidate the mechanism of LEN-enhanced RTX-mediated cytotoxicity of MCL cells. We found that LEN and RTX induced growth inhibition of both cultured and fresh primary MCL cells. LEN enhanced RTX-induced apoptosis via upregulating phosphorylation of c-Jun N-terminal protein kinases (JNK), Bcl-2, Bad; increasing release of cytochrome-c; enhancing activation of caspase-3, -8, -9 and cleavage of PARP. Meanwhile, LEN activated NK cells and increased CD16 expression on CD56lowCD16+ NK cells. Whole PBMCs but not NK cell-depleted PBMCs treated with LEN augmented 30% of RTX-dependent cytotoxicity. Daily treatment with LEN increased NK cells by 10-folds in SCID mice, and combination of LEN and RTX decreased tumor burden and prolonged survival of MCL-bearing SCID mice. Taken together, our study demonstrates that LEN plus RTX provides a synergistically therapeutic effect on MCL cells by enhancing apoptosis and RTX-dependent NK cell-mediated cytotoxicity and may be an optimal combination in the clinical trial of relapsed or refractory MCL. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source]

2211: The utility of a rabbit model of adenovirus ocular infection

Acute adenovirus ocular infections are the most common ocular viral infections worldwide and are associated with community and medical facility epidemics. While not permanently blinding, ocular adenoviral infections are associated with significant patient morbidity, including symptomatic distress with visual disturbances which can last years, and loss of time from school or work. Currently, the treatment of these acute infections is symptomatic due to the lack of an approved antiviral. This symptomatic treatment presents a controversy of whether to treat these viral infections with immunomodulating agents (e.g. topical corticosteroids, NSAIDs, cyclosporine A), which are contraindicated for use in the treatment of the other major external ocular viral infection, HSV-1 epithelial keratitis. The adenovirus type 5 (Ad5)/New Zealand White (NZW) rabbit ocular model has provided data for potential clinical guidelines for the use of immunomodulating agents in the treatment of adenovirus ocular infections. Moreover, this model has been used extensively to evaluate promising candidate antivirals for adenovirus. Multiple candidate antivirals have been evaluated in vivo using this model, and several have proceeded to human clinical trials. The current presentation will discuss the potential clinical guidelines for the use of immunomodulating agents, present data on potential new topical antiviral agents, discuss the potential combination therapy of an antiviral and immunomodulatory agent in the treatment of adenovirus ocular infections as well as the limitations of the model. Commercial interest [source]

Human herpesviruses-6, -7 and -8 in organ transplant recipients

N. Singh
The newer herpesviruses are being increasingly recognized as significant opportunistic pathogens in organ transplant recipients. Published data support the role of human herpesvirus-6 as a potential cause of encephalitis and bone marrow suppression in transplant setting. An association of human herpesvirus-6 with fungal infections and cytomegalovirus infection has also been documented. Human herpesvirus-7 also appears to be an immunomodulatory agent and may facilitate the pathogenicity of cytomegalovirus. Unlike human herpesviruses -6 and -7, human herepsvirus -8 is not ubiquitous; its seroprevalence exhibits wide geographic variation. Human herpesvirus-8 has been causally associated with post-transplant Kaposi's sarcoma. The complete spectrum of pathogenicity and ultimately the effective prophylaxis and management of these viruses has yet to be fully elucidated. [source]

Effect of intermediate-purity factor VIII (FVIII) concentrate on lymphocyte proliferation and apoptosis: transforming growth factor-, is a significant immunomodulatory component of FVIII

G. Hodge
Factor concentrates have been shown to have a variety of immunomodulatory effects in vitro. The presence of plasma-derived factor VIII (pdFVIII) has been shown to diminish lymphocyte proliferative response to mitogens. Recently, we have shown the presence of transforming growth factor-, (TGF-,) as an immunomodulatory component present in plasma-derived FVIII concentrate. However, the addition of neutralizing antibody to TGF-, did not abrogate the inhibitory effect of pdFVIII on monocyte cytokine production, suggesting the presence of other, as yet undetermined, immunomodulatory agent/s in pdFVIII. To further characterize the immunomodulatory effects of pdFVIII, the in vitro effect of pdFVIII concentrate on proliferation and apoptosis of mitogen-stimulated T cells was studied using whole blood and purified T cells. The presence of pdFVIII increased the apoptosis of phytohaemagglutinn (PHA) -stimulated CD4 and CD8 T-cell subsets as determined by Annexin V binding and DNA fragmentation. T-cell subsets showed a pdFVIII dose-dependent inhibition of entry into S-phase and G1 arrest. Addition of neutralizing anti-TGF-, reduced some of these changes. To determine the physiological relevance of these findings, blood samples from five patients receiving FVIII prophylaxis were similarly studied ex vivo and showed significantly increased apoptosis of T-cell subsets as determined by Annexin V staining. TGF-, has been reported to be a potent inhibitor of T-cell proliferation, arresting the cell cycle in G1 phase and causing apoptosis. Together, these findings suggest that TGF-, is a significant immunomodulatory component of pdFVIII concentrates. [source]

Update on therapeutic options in Waldenström macroglobulinemia

Xavier Leleu
Abstract Waldenström macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells (LPCs), along with demonstration of an IgM monoclonal gammopathy in the blood. WM remains incurable, with 5,6 yr median overall survival for patients with symptomatic WM. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab, either in monotherapy or in combination. Studies involving combination chemotherapy are ongoing, and preliminary results are encouraging. However, there are several limitations to these approaches. The complete response rate is low and the treatment free survival are short in many patients, no specific agent or regimen has been shown to be superior to another, and no treatment has been specifically approved for WM. As such, novel therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to develop new targeted therapeutics for this malignancy. These efforts have led to the development of proteasome inhibitors, of them bortezomib, several Akt/mTor inhibitors, such as perifosine and Rad001, and immunomodulatory agents such as thalidomide and lenalidomide. Many agents and monoclonal antibodies are currently being tested in clinical trials and seem promising. This report provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM. [source]

Efficacy of infliximab in refractory pouchitis and Crohn's disease-related complications of the pouch: A Belgian case series

Marc Ferrante MD
Abstract Background: Up to 25% of inflammatory bowel disease (IBD) patients undergoing surgery with an ileal pouch,anal anastomosis (IPAA) will develop chronic pouchitis not responding to antibiotics. In case reports, thiopurine analogs and infliximab (IFX) have been proposed as effective therapy in this setting. We analyzed the long-term efficacy of IFX in Belgian patients with refractory pouch complications. Methods: We identified 28 IPAA patients who received IFX for refractory luminal inflammation (pouchitis and/or pre-pouch ileitis, n = 25) and/or pouch fistula (n = 7). Patients with elements of Crohn's disease after review of the colectomy specimen were excluded. Clinical response was defined as complete in case of cessation of diarrhea, blood loss, and abdominal pain, and as partial in case of marked clinical improvement. Fistula response was defined as complete in case of cessation and as partial in case of reduction of fistula drainage. Results: Eighty-two percent of patients were concomitantly treated with immunomodulatory agents. At week 10 following start of IFX, 88% of patients with refractory luminal inflammation showed clinical response (14 partial, 8 complete), while 6 patients (86%) showed fistula response (3 partial, 3 complete). The mPDAI dropped significantly from 9.0 (interquartile range [IQR] 8.0,10.0) to 4.5 (3.0,7.0) points (P < 0.001). After a median follow-up of 20 (7,36) months, 56% showed sustained clinical response while 3 out of 7 fistula patients showed sustained fistula response. Five patients needed permanent ileostomy. Conclusions: In this series, IFX was effective long-term in IPAA patients with refractory luminal inflammation and pouch fistula. These results warrant a prospective multicenter randomized controlled trial. Inflamm Bowel Dis 2009 [source]

Pararenal retroperitoneal Castleman's disease mimicking systemic lupus erythematosus

Abstract A 41-year-old man diagnosed initially as probable systemic lupus erythematosus (SLE) visited our hospital complaining of a persistent painful oral ulcer and multiple spots like coffee beans on his trunk. Antibodies except for anti-dsDNA and anti-histone antibodies and other serologies were negative. Conventional cytotoxic and immunomodulatory agents did not have any effect on these lesions. Computed tomography for evaluating persistent dry cough incidentally showed a huge mass in the left mid-retroperitoneum. Surgical treatment was done and the final diagnosis was Castleman's disease (CD). CD is a relatively rare disorder characterized by a massive non-malignant tumor of lymphoid tissues, with unknown etiology. It commonly presents as a localized soft tissue mass within the mediastinum or neck, and rarely in the retroperitoneal space. Since some cases of CD may share systemic, immune and histopathologic features of autoimmune disease, exact diagnosis is difficult to make based on the clinical and laboratory clues alone. We report herein an unusual case with pararenal retroperitoneal CD mimicking SLE. [source]

Management of complications after implantation of fillers

Koenraad De Boulle
Summary Soft tissue augmentation is widely practised by a variety of different practitioners. A new classification of filler substances and procedures, taking into account long-term safety and reversibility of side effects, is proposed: i non-permanent and biodegradable, ii,semi-permanent and biodegradable, iii,permanent and reversible, iv,permanent and non-reversible. Complications and adverse effects occur with all fillers and all filler procedures. Insufficient experience is an important contributory factor. Underreporting is probably common. Commonest are haematomas, ecchymoses, infections, papulopustular or acneiform lesions, non-hypersensitivity related swelling and oedema, erythema, changes in pigmentation, palpability of the implant and necrosis of overlying tissue. Specific therapeutic approaches for these complications and practical recommendations to minimize or avoid them are discussed. Hypersensitivity reactions and granuloma formation are the most distressing adverse effects. They can occur with most fillers. Mostly these hypersensitivity reactions are local granulomas but, rarely, generalized reactions also occur. Case reports of systemic reactions after injection of hyaluronic acid are documented. Treatments include steroids, minocycline and immunomodulatory agents, such as cyclosporin, tacrolimus and ascomycin. In selected cases, surgical procedures are necessary to elimirate granulomatous reactions. Implant migration and facial lipoatrophy are encountered with certain compounds. Extreme caution is therefore advocated before using permanent and non-reversible products for soft tissue augmentation. Those who use fillers need to be familiar with the complications of fillers and with the treatment of those complications. [source]

Is Gadolinium Enhancement Predictive of the Development of Brain Atrophy in Multiple Sclerosis?

A Review of the Literature
ABSTRACT Background and Purpose. Several studies have demonstrated that brain atrophy can be detected over relatively short intervals from the earliest stages of multiple sclerosis (MS). Reviewing the published data, the authors highlight some hypothetical pathological mechanisms proposed as determinants of brain atrophy. Methods. Using the terms multiple sclerosis, MRI (magnetic resonance imaging), and brain atrophy, 181 citations were identified. The authors considered only studies with prospective designs with natural-course MS patients and/or placebo-treated patients of therapeutic trials, in which patients under-went baseline and follow-up scans with a T1-weighted gadolinium diethylenetriamine penta-acetic acid sequence (0.1 mmol/kg body weight), and correlation analyses between Gd enhancement activity and brain atrophy progression. Results. Five hundred thirty-two patients of 5 natural history studies and 5 therapeutic trial studies participated in the review process. The main observation was that in patients with a relapsing-remitting (RR) disease course, there was a correlation between Gd enhancement activity and brain atrophy progression. This correlation was not influenced by any other demographic and clinical additional data considered in the review process. Conclusions. Examination of the pathological mechanisms pro-posed in the reviewed studies led the authors to believe that inflammation is only in part responsible for the development of brain atrophy. This conclusion may have an implication for the strategies of tissue protection advocated in the early stages of the RR course and strengthen recent evidence indicating that anti-inflammatory immunomodulatory agents and immunosuppressive treatments, which predominantly act against the inflammatory component of disease activity, may not have similar effects on progressive tissue loss, either in RR or progressive MS. [source]

Practical aspects of management of recurrent aphthous stomatitis

A Altenburg
Treatment of recurrent aphthous stomatitis (RAS) remains, to date, empirical and non-specific. The main goals of therapy are to minimize pain and functional disabilities as well as decrease inflammatory reactions and frequency of recurrences. Locally, symptomatically acting modalities are the standard treatment in simple cases of RAS. Examples include topical anaesthetics and analgesics, antiseptic and anti-phlogistic preparations, topical steroids as cream, paste or lotions, antacids like sucralfate, chemically stable tetracycline suspension, medicated toothpaste containing the enzymes amyloglucosidase and glucoseoxidase in addition to the well-known silver nitrate application. Dietary management supports the treatment. In more severe cases, topical therapies are again very useful in decreasing the healing time but fail to decrease the interval between attacks. Systemic immunomodulatory agents, like colchicine, pentoxifylline, prednisolone, dapsone, levamisol, thalidomide, azathioprine, methotrexate, cyclosporin A, interferon alpha and tumour necrosis factor (TNF) antagonists, are helpful in resistant cases of major RAS or aphthosis with systemic involvement. [source]

Immunotherapy of idiopathic inflammatory neuropathies

MUSCLE AND NERVE, Issue 3 2003
Peter D. Donofrio MD
Abstract Evaluation of peripheral neuropathy is a common reason for referral to a neurologist. Recent advances in immunology have identified an inflammatory component in many neuropathies and have led to treatment trials using agents that attenuate this response. This article reviews the clinical presentation and treatment of the most common subacute inflammatory neuropathies, Guillain,Barré syndrome (GBS) and Fisher syndrome, and describes the lack of response to corticosteroids and the efficacy of treatment with plasma exchange and intravenous immunoglobulin (IVIG). Chronic inflammatory demyelinating polyneuropathy, although sharing some clinical, electrodiagnostic, and pathologic similarities to GBS, improves after treatment with plasma exchange and IVIG and numerous immunomodulatory agents. Controlled trials in multifocal motor neuropathy have shown benefit after treatment with IVIG and cyclophosphamide. Also discussed is the treatment of less common inflammatory neuropathies whose pathophysiology involves monoclonal proteins or antibodies directed against myelin-associated glycoprotein or sulfatide. Little treatment data exist to direct the clinician to proper management of rare inflammatory neuropathies resulting from osteosclerotic myeloma; POEMS syndrome; vasculitis; Sjögren's syndrome; and neoplasia (paraneoplastic neuropathy). Muscle Nerve 28: 273,292, 2003 [source]

Treatment of polymorphic light eruption

Tsui C. Ling
Polymorphic light eruption (PLE) is a highly prevalent photosensitivity disorder, estimated to affect 11,21% people in temperate countries. Typically, PLE appears as a recurrent pruritic eruption comprising papules and/or vesicles and/or plaques, which occurs on photo-exposed skin sites following sun exposure, and which heals without scarring. Commoner in females, the aetiology is uncertain, although there is evidence of an immune basis. We perform a review of the prophylaxis and treatment of this condition. While sun protection, corticosteroids and desensitization phototherapy are the mainstays of management, a range of anti-inflammatory and immunomodulatory agents are reported. [source]

ORIGINAL ARTICLE: HLA-G Expression Is Up-Regulated by Progesterone in Mesenchymal Stem Cells

Ekaterina Ivanova-Todorova
Problem, Maternal immune response to fetal tissues is modified in such way that it favors the development of pregnancy. Human leukocyte antigen (HLA)-G, progesterone and mesenchymal stem cells (MSCs) have been identified as potent immunomodulatory agents in different experimental systems and the interactions between these three factors are studies in this paper. Method of study, Human MSCs are isolated from human adipose tissue, bone marrow and decidua are cultured in the presence of progesterone and the expression of HLA-G is followed-up at protein and mRNA levels. Results, The MSCs cultured in the presence of progesterone express increased levels of both cell surface and cytoplasmic HLA-G when compared with the control MSCs. Conclusion, Progesterone up-regulates the expression by MSCs of HLA-G which is a major player in maintenance of the immune balance between the mother and the fetus. MSCs are newly detected targets of progesterone with well documented immunomodulatory activity. [source]

RGS4 Controls Renal Blood Flow and Inhibits Cyclosporine-Mediated Nephrotoxicity

A. Siedlecki
Calcineurin inhibitors (CNI) are powerful immunomodulatory agents that produce marked renal dysfunction due in part to endothelin-1-mediated reductions in renal blood flow. Ligand-stimulated Gq protein signaling promotes the contraction of smooth muscle cells via phospholipase C,-mediated stimulation of cytosolic calcium release. RGS4 is a GTPase activating protein that promotes the deactivation of Gq and Gi family members. To investigate the role of G protein-mediated signaling in the pathogenesis of CNI-mediated renal injury, we used mice deficient for RGS4 (rgs4,/,). Compared to congenic wild type control animals, rgs4,/, mice were intolerant of the CNI, cyclosporine (CyA), rapidly developing fatal renal failure. Rgs4,/, mice exhibited markedly reduced renal blood flow after CyA treatment when compared to congenic wild type control mice as measured by magnetic resonance imaging (MRI). Hypoperfusion was reversed by coadministration of CyA with the endothelin antagonist, bosentan. The MAPK/ERK pathway was activated by cyclosporine administration and was inhibited by cotreatment with bosentan. These results show that endothelin-1-mediated Gq protein signaling plays a key role in the pathogenesis of vasoconstrictive renal injury and that RGS4 antagonizes the deleterious effects of excess endothelin receptor activation in the kidney. [source]

Reduction of vascular smooth muscle cell proliferation by immunomodulation

Y. C. Chan
Background: Immunological factors may play an important role in mediating the progression of atherosclerosis and myointimal hyperplasia, with heat shock proteins being implicated as possible autoantigens. The authors have shown previously that immunomodulation can reduce vascular smooth muscle cell (vSMC) proliferation following balloon injury to rat carotid arteries. The aim of the present study was to examine the effects of immunomodulatory agents on the proliferation of rat aortic vSMCs remote from the area of balloon injury. The agents used were SRL172 (heat-killed Mycobacterium vaccae) and heat shock protein 65 kDa (HSP65) in Freund's incomplete adjuvant. Both these agents are known to influence T-cell responses. Methods: Male Sprague,Dawley rats were used. All immunizations were given subcutaneously. Four groups were studied (ten animals in each group): group 1 animals were immunized with normal saline, group 2 received SRL172, group 3 SRL172 and HSP65,Freund's, and group 4 HSP65,Freund's. Three immunizations were performed as well as carotid balloon injury. Three animals died, leaving 37 for analysis. Some 5 weeks later the animals were killed and the aorta was harvested. Standard explant techniques were applied to grow aortic vSMCs until confluency, passaged three times, quiesced, and fetal calf serum (FCS) of varying concentrations (0·4,10 per cent) was then added, incubated for another 48 h and cell counts carried out. Results: The proliferation rate of aortic vSMCs in the control group was significantly greater than that in the other study groups (Fig.). While all the treatment groups had significantly less proliferation compared with the control group (*P < 0·05, ,P < 0·01, Mann,Whitney U test), no statistically significant differences existed between any of the study groups. Conclusion: Immunomodulation may result in a reduction of vSMC proliferation. Although the precise mechanisms involved are unclear, these results are in concordance with previous findings that T-cell immunomodulation decreases the development of myointimal hyperplasia after injury, and suggest that a fundamental phenotypic shift has been produced by these immunizations. [source]