Rat Cytomegalovirus Vaccine Prevents Accelerated Chronic Rejection in CMV-Naïve Recipients of Infected Donor Allograft Hearts

Streblow, Daniel N.; Hwee, Y.; Kreklywich, Craig N.; Andoh, Takeshi F.; Denton, Michael; Smith, Patricia P.; Hart, E.; Broekel, R.; Pallett, C.; Rogers, Kelsey S.; Streblow, Aaron D; Chuop, Maria; Perry, Amanda R.; Messaoudi, Ilhem; Orloff, Susan L.

doi:10.1111/ajt.13188

Cited by 16 publications

(15 citation statements)

References 46 publications

(66 reference statements)

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“…Animal models of HCMV infection including rodents, guinea pigs, and non-human primates have provided data consistent with the importance of adaptive immunity and the control of HCMV [ 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ]. These models have utilized a variety of approaches to define the relative contribution of HCMV-specific T lymphocyte responses and antiviral antibodies in the control of species-specific CMV infections under the conditions of immune suppression that mimic those following transplantation in humans and lentivirus infections that model HIV/AIDS [ 78 , 79 ].…”

Section: Evidence That Adaptive Immunity Can Modify But Not Prevenmentioning

confidence: 85%

Maternal Immunity and the Natural History of Congenital Human Cytomegalovirus Infection

Britt

2018

Viruses

102

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Congenital human cytomegalovirus (HCMV) is the most common viral infection of the developing fetus, and a significant cause of neurodevelopmental abnormalities in infants and children. Congenital HCMV infections account for an estimated 25% of all cases of hearing loss in the US. It has long been argued that maternal adaptive immune responses to HCMV can modify both the likelihood of intrauterine transmission of HCMV, and the severity of fetal infection and risk of long term sequelae in infected infants. Over the last two decades, multiple studies have challenged this paradigm, including findings that have demonstrated that the vast majority of infants with congenital HCMV infections in most populations are born to women with established immunity prior to conception. Furthermore, the incidence of clinically apparent congenital HCMV infection in infants born to immune and non-immune pregnant women appears to be similar. These findings from natural history studies have important implications for the design, development, and testing of prophylactic vaccines and biologics for this perinatal infection. This brief overview will provide a discussion of existing data from human natural history studies and animal models of congenital HCMV infections that have described the role of maternal immunity in the natural history of this perinatal infection.

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Section: Evidence That Adaptive Immunity Can Modify But Not Prevenmentioning

confidence: 85%

Maternal Immunity and the Natural History of Congenital Human Cytomegalovirus Infection

Britt

2018

Viruses

102

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“…The rat model has been useful in studying vascular disease and solid organ transplant rejection resulting from RCMV infection [177]. An H 2 O 2 -inactivated RCMV strain was investigated, resulting in a time-to-rejection delay of cardiac allograft; however the timing of the vaccine was important in terms of providing protection to the allograft recipient [178]. This vaccine evoked a protective response by preventing transplant vascular sclerosis brought on by RCMV infection and extended graft survival to control levels; however, it was not reported to prevent the virus from reactivation.…”

Section: Animal Models and Cmv: Vaccine Implicationsmentioning

confidence: 99%

A fifty-year odyssey: prospects for a cytomegalovirus vaccine in transplant and congenital infection

Diamond

Rosa

Chiuppesi

et al. 2018

Expert Review of Vaccines

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Introduction: It has been almost fifty years since the Towne strain was used by Plotkin and collaborators as the first vaccine candidate for cytomegalovirus (CMV). While that approach showed partial efficacy, there have been a multitude of challenges to improve on the promise of a CMV vaccine. Efforts have been dichotomized into a therapeutic vaccine for patients with CMV-infected allografts, either stem cells or solid organ, and a prophylactic vaccine for congenital infection. Areas Covered: This review will evaluate research prospects for a therapeutic vaccine for transplant recipients that recognizes CMV utilizing primarily T cell responses. Similarly, we will provide an extensive discussion on attempts to develop a vaccine to prevent the manifestations of congenital infection, based on eliciting a humoral anti-CMV protective response. The review will also describe newer developments that have upended the efforts towards such a vaccine through the discovery of a second pathway of CMV infection that utilizes an alternative receptor for entry using a series of antigens that have been determined to be important for prevention of infection. Expert Commentary: There is a concerted effort to unify separate therapeutic and prophylactic vaccine strategies into a single delivery agent that would be effective for both transplant-related and congenital infection.

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“…In the current study, we modeled one scenario in which the non-self antigen was restricted to hematopoietic cells, as would occur in EBV infection (25). In another example, recipients may be intentionally vaccinated against donor-derived pathogens, such as CMV, and then transplanted with pathogen-infected donor organs (56). An inadvertent consequence of eliciting protective CMV-reactive immune memory is that ‘linked antigen’ reactivity could incite graft rejection in the immune host.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Transplant Tolerance by an “Incognito” Form of CD8 T Cell–Dependent Memory

Nelsen

Beard

Plenter

et al. 2017

American Journal of Transplantation

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Several approaches successfully achieve allograft tolerance in preclinical models but are challenging to translate into clinical practice. Many clinically relevant factors can attenuate allograft tolerance induction including intrinsic genetic resistance, peri-transplant infection, inflammation, and pre-existing anti-donor immunity. The prevailing view for immune memory as a tolerance barrier is that the host harbors memory cells that spontaneously cross-react to donor MHC antigens. Such pre-existing ‘heterologous’ memory cells have direct reactivity to donor cells and resist most tolerance regimens. In this study, we developed a model system to determine if an alternative form of immune memory could also block tolerance. We posited that host memory T cells could potentially respond to donor-derived non-MHC antigens, such as latent viral antigens or autoantigens, to which the host is immune. Results show that immunity to a model non-self antigen, ovalbumin (OVA), can dramatically disrupt tolerance despite undetectable initial reactivity to donor MHC antigens. Importantly, this blockade of tolerance was CD8 T cell-dependent and required linked antigen presentation of alloantigens with the test OVA antigen. As such, this pathway represents an unapparent, or ‘incognito,’ form of immunity that is sufficient to prevent tolerance and that can be an unforeseen additional immune barrier to clinical transplant tolerance.

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Rat Cytomegalovirus Vaccine Prevents Accelerated Chronic Rejection in CMV-Naïve Recipients of Infected Donor Allograft Hearts

Cited by 16 publications

References 46 publications

Maternal Immunity and the Natural History of Congenital Human Cytomegalovirus Infection

Maternal Immunity and the Natural History of Congenital Human Cytomegalovirus Infection

A fifty-year odyssey: prospects for a cytomegalovirus vaccine in transplant and congenital infection

Disruption of Transplant Tolerance by an “Incognito” Form of CD8 T Cell–Dependent Memory

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