Mechanistic Study of Malononitrileamide FK778 in Cardiac Transplantation and CMV Infection in Rats

Zeng, Huasong; Waldman, W. James; Yin, Deng Ping; Knight, Deborah; Shen, Jikun; Ma, Lianli; Meister, Gabriel T.; Chong, Anita S.; Williams, James W.

doi:10.1097/01.tp.0000137334.46155.94

Cited by 33 publications

(30 citation statements)

References 31 publications

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“…Acute infection with rat (R)CMV accelerates TVS in rat organ transplantation, leading to graft failure (29,35,38). Similar to the clinical scenario, antiviral therapy reduces the acceleration of rejection, underscoring the need for viral replication (42,48). Importantly, the effects of RCMV on TVS acceleration are not organ type specific but occur in various solid organs (29,35,38,43).…”

mentioning

confidence: 94%

Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

Dumortier

Streblow

Moses

et al. 2008

J Virol

102

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Human cytomegalovirus (HCMV) is implicated in the acceleration of a number of vascular diseases including transplant vascular sclerosis (TVS), the lesion associated with chronic rejection (CR) of solid organ transplants. Although the virus persists in the allograft throughout the course of disease, few cells are directly infected by CMV. This observation is in contrast to the global effects that CMV has on the acceleration of TVS/CR, suggesting that CMV infection indirectly promotes the vascular disease process. Recent transcriptome analysis of CMV-infected heart allografts indicates that the virus induces cytokines and growth factors associated with angiogenesis (AG) and wound healing (WH), suggesting that CMV may accelerate TVS/CR through the induction and secretion of AG/WH factors from infected cells. We analyzed virus-free supernatants from HCMV-infected cells (HCMV secretomes) for growth factors, by mass spectrometry and immunoassays, and found that the HCMV secretome contains over 1,000 cellular proteins, many of which are involved in AG/WH. Importantly, functional assays demonstrated that CMV but not herpes simplex virus secretomes not only induce AG/WH but also promote neovessel stabilization and endothelial cell survival for 2 weeks. These findings suggest that CMV acceleration of TVS occurs through virus-induced growth factors and cytokines in the CMV secretome.Numerous epidemiological and animal studies link human cytomegalovirus (HCMV) to the acceleration of vascular diseases including arterial restenosis, atherosclerosis, and transplant vascular sclerosis (TVS) (23,24,37). Recent advances in transplantation have significantly impacted short-term allograft and patient survival; however, long-term graft survival has not improved, due largely to chronic rejection (CR). The prevalence of CR is a concern, since retransplantation is the sole effective therapy. TVS represents the hallmark of CR in vascularized solid organ transplants, and HCMV infection nearly doubles the 5-year rate of cardiac graft failure due to accelerated TVS (11). In heart transplant recipients, ganciclovir, a potent inhibitor of CMV replication, delays the time to allograft rejection (25, 44). A higher incidence of viral DNA in the explant vascular intima from patients with cardiac allograft TVS than in explants without vasculopathy further underscores the influence of HCMV on CR development (47). In kidney transplant patients, the presence of HCMV infection, whether asymptomatic or displaying overt symptoms, negatively impacts allograft survival (9). The role of HCMV in TVS/CR development is clear; however, the mechanisms involved in this process remain illusive for the following reasons: HCMV disease etiology is multifactorial; HCMV is ubiquitous throughout the human population; HCMV infection is lifelong and infects all of the cell types involved in TVS, including smooth muscle cells (SMC), endothelial cells (EC), and macrophages; and HCMV evades the immune system by remaining latent, and clinically silent reactivation is diffic...

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mentioning

confidence: 94%

Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

Dumortier

Streblow

Moses

et al. 2008

J Virol

102

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“…For example, in rat solid organ transplantation, acute infection with rat (R)CMV infection accelerates TVS, which leads to untimely graft failure (Orloff et al 2002;Streblow et al 2003;Soule et al 2006). Similar to the human transplantation setting antiviral therapy reduces the acceleration of rejection in rat transplant models demonstrating that active CMV replication is required for these disease processes (Tikkanen et al 2001a;Zeng et al 2005). Importantly, the effects of RCMV on the acceleration of TVS are not organ-type specific but can occur in a broad range of solid organ transplants including heart, kidney, lung, and small bowel (Tikkanen et al 2001b;Orloff et al 2002;Streblow et al 2003;Soule et al 2006).…”

Section: Animal Models Of Cmv-accelerated Graft Rejectionmentioning

confidence: 99%

Mechanisms of Cytomegalovirus-Accelerated Vascular Disease: Induction of Paracrine Factors That Promote Angiogenesis and Wound Healing

Streblow

Dumortier

Moses

et al. 2008

Current Topics in Microbiology and Immunology

108

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Human cytomegalovirus (HCMV) is associated with the acceleration of a number of vascular diseases such as atherosclerosis, restenosis, and transplant vascular sclerosis (TVS). All of these diseases are the result of either mechanical or immune-mediated injury followed by inflammation and subsequent smooth muscle cell (SMC) migration from the vessel media to the intima and proliferation that culminates in vessel narrowing. A number of epidemiological and animal studies have demonstrated that CMV significantly accelerates TVS and chronic rejection (CR) in solid organ allografts. In addition, treatment of human recipients and animals alike with the antiviral drug ganciclovir results in prolonged survival of the allograft indicating that CMV replication is a requirement for acceleration of disease. However, although virus persists in the allograft throughout the course of disease, the number of directly infected cells does not account for the global effects that the virus has on the acceleration of TVS and CR. Recent investigations of up-and down-regulated cellular genes in infected allografts in comparison to native heart has demonstrated that Rat-CMV (RCMV) up-regulates genes involved in wound healing (WH) and angiogenesis (AG). Consistent with this result, we have found that supernatants from HCMV infected cells (HCMV secretome) induce WH and AG using in vitro models. Taken together these findings suggest that one mechanism for HCMV acceleration of TVS is mediated through induction of secreted cytokines and growth factors from virus-infected cells that promote WH and AG in the allograft, resulting in the acceleration of TVS. We review here the ability of CMV infection to alter the local environment by producing cellular factors that act in a paracrine fashion to enhance WH and AG processes associated with the development of vascular disease, which accelerates chronic allograft rejection.

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“…The malononitrilamide FK778 is a new class of low-molecular-weight immunosuppressive agents. Previous in vitro studies have demonstrated FK778's capacity to block proliferative responses, antibody production and, more recently, its inhibitory effect on the cytomegalovirus (25)(26).…”

Section: Discussionmentioning

confidence: 99%

Role of FK778 Alone or in Combination with Tacrolimus or mTOR Inhibitors as an Immunomodulator of Immunofunctions: In Vitro Evaluation of T Cell Proliferation and the Expression of Lymphocyte Surface Antigens

Millán

Jiménez²,

Fortuna³

et al. 2006

Int J Immunopathol Pharmacol

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We evaluated the in vitro capacity of FK778, alone or in combination with other immunosuppressive drugs: Tacrolimus (TRL); Sirolimus (SRL), Everolimus (EVL), to inhibit clonal expansion of Tlymphocytes and expression of lymphocyte-activation surface antigens; secondly, we compared the immunosuppressive potential of FK778 combined with TRL, SRL and EVL with the same combinations using Mycophenolic acid (MPA) as antimetabolite. Lymphocyte proliferation was assessed by 3H_ Thymidine incorporation, in whole blood cultures stimulated with ConA. The effect of FK778 on alloresponse was evaluated by MLC and the expression of lymphocyte surface antigens by cytometry. FK778, TRL, SRL and EVL showed a high in vitro capacity to inhibit lymphocyte proliferation in a concentration-dependent way. Combinations of FK778 with TRL, SRL, or EVL presented an additive effect, especially FK778+TRL. Similar inhibition capacity of the clonal expansion was observed, when FK778 was combined with TRL, SRL or EVL, respecting the same combinations but using MPA instead of FK778. In addition, FK778 inhibited the expression of lymphocyte surface antigens involved in activation, co-stimulatory and apoptosis signals. In conclusion, FK778 inhibits the proliferative response induced by mitogeneic and allogeneic stimuli and the expression of surface antigens. Combinations of FK778 with TRL or mTOR inhibitors presented an additive effect and their action on T cell proliferation was similar to that of combinations with MPA. Since FK778, TRL and mTOR inhibitors present different action mechanisms and involve different cellular targets, these combinations may help prevent episodes of allorejection in organ transplants. FK778 and mTOR inhibitors may represent an alternative treatment for patients with renal failure.Over the past two decades many immunosuppressive drugs, such as calcineurin inhibitors (cyclosporine, tacrolimus), antimetabolites (azathioprine, mycophenolate mofetil), mTOR inhibitors (sirolimus, everolimus), and monoclonal antibodies to T lymphocytes (basiliximab, daclizumab, CD3) have been approved for clinical use in the prevention of graft rejection in solid organ transplants.Though notable progress has been achieved in short-term graft survival rates and in the prevention of acute rejection by specific combinations of these immunosuppressive agents, long-term outcomes of

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Mechanistic Study of Malononitrileamide FK778 in Cardiac Transplantation and CMV Infection in Rats

Cited by 33 publications

References 31 publications

Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

Mechanisms of Cytomegalovirus-Accelerated Vascular Disease: Induction of Paracrine Factors That Promote Angiogenesis and Wound Healing

Role of FK778 Alone or in Combination with Tacrolimus or mTOR Inhibitors as an Immunomodulator of Immunofunctions: In Vitro Evaluation of T Cell Proliferation and the Expression of Lymphocyte Surface Antigens

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