Both Mucosal and Systemic Routes of Immunization with the Live, Attenuated NYVAC/Simian Immunodeficiency Virus SIVgpe Recombinant Vaccine Result in Gag-Specific CD8+ T-Cell Responses in Mucosal Tissues of Macaques

Harvard University, Cambridge, Massachusetts, United States
Journal of Virology (Impact Factor: 4.44). 12/2002; 76(22):11659-76. DOI: 10.1128/JVI.76.22.11659-11676.2002
Source: PubMed


As most human immunodeficiency virus (HIV) infection occurs via mucosal surfaces, an important goal of vaccination may be
the induction of virus-specific immune responses at mucosal sites to contain viral infection early on. Here we designed a
study in macaques carrying the major histocompatibility complex class I Mamu-A∗01 molecule to assess the capacity of the highly
attenuated poxvirus NYVAC/simian immunodeficiency virus (SIV) SIVgpe vaccine candidate administered by the intranasal, intramuscular, or intrarectal route to induce mucosal immunity. All macaques,
including one naive macaque, were exposed to SIVmac251 by the intrarectal route and sacrificed 48 h after infection. The kinetics of immune response at various time points following
immunization with NYVAC/SIVgpe and the anamnestic response to SIVmac251 at 48 h after challenge were assessed in blood, in serial rectal and vaginal biopsy samples, and in tissues at euthanasia
with an SIVmac Gag-specific tetramer. In addition, at euthanasia, antigen-specific cells producing gamma interferon or tumor necrosis factor
alpha from the jejunum lamina propria were quantified in all macaques. Surprisingly, antigen-specific CD8+ T cells were found in the mucosal tissues of all immunized macaques regardless of whether the vaccine was administered by
a mucosal route (intranasal or intrarectal) or systemically. In addition, following mucosal SIVmac251 challenge, antigen-specific responses were mainly confined to mucosal tissues, again regardless of the route of immunization.
We conclude that immunization with a live vector vaccine results in the appearance of CD8+ T-cell responses at mucosal sites even when the vaccine is delivered by nonmucosal routes.

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    • "Despite clear evidence for the imprinting of a specific homing pattern during T cell priming, this elegant model likely has certain limitations, as several experimental studies of infectious diseases have shown wider recirculation pattern and substantial promiscuity in the trafficking programing, as well as a surprisingly flexible tissue distribution of in vivo-induced SLECs (24–26). However, large or biased homing patterns observed in some models could be due to several immune and pathogen-related factors: (i) in vivo model used, (ii) artifacts related to high number transfer of Ag-specific transgenic T cells (iii) low level of induction of broad-spectrum homing molecules such as mucosal T cells-associated marker α4β7 integrin or inflammation-related molecules (iv) immunization route (v) priming such as Ag load, priming threshold, adjuvants and costimulation, polarization, or regulatory signals, and (vi) target tissue-analyzed (more promiscuous, mucosa-associated, and more restricted skin-specific homing pattern), among others (24–29). "
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    ABSTRACT: T cell immunity is characterized by striking tissue specialization. Tissue-specificity imprinting starts during priming by tissue-derived migratory dendritic cells in the non-random, specialized micro-anatomical area of the draining lymph node and is influenced by constitutive and induced cues from local environment. Besides tissue-specific effectors, memory cells also exhibit a tissue-specificity. Long-lived tissue-resident memory T cells likely play a considerable role in preventing pathogen invasion. Understanding of the mechanisms of tissue specialization of T cells is of major importance for the design of optimal vaccination strategies and therapeutic interventions in tissue/organ-specific inflammatory diseases. The present review summarizes our current knowledge and hypothesis about tissue-specificity imprinting and tissue residency of T cells.
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    • "Menstrual blood T cells were also shown to be functional and capable of responding to CMV, as measured by IFN-λ secretion using intracellular cytokine staining. Our data show that antigen-specific responses are reduced in T cells obtained from menstrual blood, unlike responses seen in other mucosal compartments such as breast milk and cervical and vaginal tissue [20], [21], [22]. This potential reduction in the number of antigen-specific cells in menstrual blood maybe due to a reduction in the general functional capacity of these cells as they respond to PMA/Ionomycin, but their responsiveness is also reduced when compared to PBMC (Figure 6). "
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    ABSTRACT: Studies of T cell-mediated immunity in the human female genital tract have been problematic due to difficulties associated with the collection of mucosal samples. Consequently, most studies rely on biopsies from the lower female genital tract or remnant tissue from hysterectomies. Availability of samples from healthy women is limited, as most studies are carried out in women with underlying pathologies. Menstruation is the cyclical sloughing off of endometrial tissue, and thus it should be a source of endometrial cells without the need for a biopsy. We isolated and phenotyped T cells from menstrual and peripheral blood and from endometrial biopsy-derived tissue from healthy women to determine the types of T cells present in this compartment. Our data demonstrated that T cells isolated from menstrual blood are a heterogeneous population of cells with markers reminiscent of blood and mucosal cells as well as unique phenotypes not represented in either compartment. T cells isolated from menstrual blood expressed increased levels of HLA-DR, αEβ7 and CXCR4 and reduced levels of CD62L relative to peripheral blood. Menstrual blood CD4+ T cells were enriched for cells expressing both CCR7 and CD45RA, markers identifying naïve T cells and were functional as determined by antigen-specific intracellular cytokine production assays. These data may open new avenues of investigation for cell mediated immune studies involving the female reproductive tract without the need for biopsies.
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    • "Several studies have demonstrated the ability of vaccinia-based vaccines in inducing mucosal immune responses against infectious pathogens [61–63]. For example, either mucosal or systemic routes of immunization with the live, attenuated vaccinia NYVAC/SIVgpe recombinant vaccine resulted in gag-specific CD8+ T-cell responses in mucosal tissues of macaques [49]. Furthermore, vaccines based on the MVA vector were effective in inducing protective responses against different respiratory viruses such as SARS-CoV, influenza and respiratory syncytial virus following immunization via mucosal routes [64–70]. "
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    ABSTRACT: It is well known that mucosal tissues contain the largest surface area of the human body and are the front line of natural host defense against various pathogens. In fact, more than 80% of infectious disease pathogens probably gain entry into the susceptible human hosts through open mucosal surfaces. Human immunodeficiency virus type one (HIV-1), a mainly sexually transmitted virus, also primarily targets the vaginal and gastrointestinal mucosa as entry sites for viral transmission, seeding, replication and amplification. Since HIV-1 establishes its early replication in vaginal or rectal mucosal tissues, the induction of sufficient mucosal immunity at the initial site of HIV-1 transmission becomes essential for a protective vaccine. However, despite the fact that current conventional vaccine strategies have remained unsuccessful in preventing HIV-1 infection, sufficient financial support and resources have yet to be given to develop a vaccine able to elicit protective mucosal immunity against sexual transmissions. Interestingly, Chinese ancestors invented variolation through intranasal administration about one thousand years ago, which led to the discovery of a successful smallpox vaccine and the final eradication of the disease. It is the hope for all mankind that the development of a mucosal AIDS vaccine will ultimately help control the AIDS pandemic. In order to discover an effective mucosal AIDS vaccine, it is necessary to have a deep understanding of mucosal immunology and to test various mucosal vaccination strategies.
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