Pretransplant BK Virus-Specific T-Cell-Mediated Immunity and Serotype Specific Antibodies May Have Utility in Identifying Patients at Risk of BK Virus-Associated Haemorrhagic Cystitis after Allogeneic HSCT

BK polyomavirus (BKPyV) persists lifelong in renal and urothelial cells with asymptomatic urinary shedding in healthy individuals. In some immunocompromised persons after transplantation of hematopoietic stem cells (HSCT), the BKPyV high-rate replication is associated with haemorrhagic cystitis (HC). We tested whether the status of BKPyV immunity prior to HSCT could provide evidence for the BKPyV tendency to reactivate. We have shown that measurement of pretransplant anti-BKPyV 1 and 4 IgG levels can be used to evaluate the HC risk. Patients with anti-BKPyV IgG in the range of the 1st–2nd quartile of positive values and with positive clinical risk markers have a significantly increased HC risk, in comparison to the reference group of patients with “non-reactive” anti-BKPyV IgG levels and with low clinical risk (LCR) (p = 0.0009). The predictive value of pretransplant BKPyV-specific IgG was confirmed by determination of genotypes of the shed virus. A positive predictive value was also found for pretransplant T-cell immunity to the BKPyV antigen VP1 because the magnitude of IFN-γ T-cell response inversely correlated with posttransplant DNAuria and with HC. Our novel data suggest that specific T-cells control BKPyV latency before HSCT, and in this way may influence BKPyV reactivation after HSCT. Our study has shown that prediction using a combination of clinical and immunological pretransplant risk factors can help early identification of HSCT recipients at high risk of BKPyV disease.

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Pretransplant BK virus-specific T-cell-mediated immunity and serotype specific antibodies may have utility in identifying patients at risk for BK virus associated haemorrhagic cystitis after allogeneic HSCT

10.1101/2021.06.09.21258555 ◽

2021 ◽

Author(s):

Marketa Stastna-Markova ◽

Eva Hamsikova ◽

Petr Hainz ◽

Petr Hubacek ◽

Marie Kroutilova ◽

...

Keyword(s):

At Risk ◽

T Cell ◽

Cell Response ◽

Bk Virus ◽

T Cell Response ◽

Cell Mediated Immunity ◽

Haemorrhagic Cystitis ◽

Hematopoietic Stem ◽

Specific Antibodies ◽

Clinical Risk

BK polyomavirus (BKV) persists lifelong in the urinary tract with asymptomatic urinary shedding in healthy individuals. In immunocompromised persons after transplantation of hematopoietic stem cells (HSCT) the BKV high-rate replication is associated with haemorrhagic cystitis (HC) with a reported incidence of 17 %. Numerous studies of reconstitution of the immune system after HSCT have established the principal role of T cell effectors in the control of viral replication and reactivation. The value of pretransplant BKV-specific antibodies in transplanted patients for the protection from viral disease was long considered insignificant. We hypothesized that the status of BKV immunity prior to HSCT could provide evidence for the BKV tendency to reactivate and that examining the level of subtype-specific antibodies and T-cell response in individual patients could help to predict the risk of BKV reactivation and HC. Evaluation of the risk of HC in relation to pretransplant anti-BKV1,2,4 IgG levels together with clinical factors known before transplantation revealed that patients with medium anti-BKV IgG and significant clinical risk (SR) have a very significantly increased HC risk in comparison with the reference group of low anti-BKV IgG level and low clinical risk (LR) (P=0.0009). Analysis of pretransplant T cell immunity to BKV antigens VP1 and LTag has shown that magnitude of IFN-gamma T cell response inversely corelated with posttransplant DNAuria. We hypothesize that the control of BKV latency by BKV specific T cells before HSCT would be one of the factors that influence BKV reactivation after HSCT. Our study has shown that prediction using a combination of clinical and immunological pretransplant risk factors can help early identification of patients who are at risk of developing BKV disease after HSCT.

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Role of Virus-Specific T cell therapy for Cytomegalovirus and BK infections in kidney transplant recipients

Kidney360 ◽

10.34067/kid.0001572021 ◽

2021 ◽

pp. 10.34067/KID.0001572021

Author(s):

Sandesh Parajuli ◽

Margaret R. Jorgenson ◽

Ross O. Meyers ◽

Arjang Djamali ◽

Jacques Galipeau

Keyword(s):

Kidney Transplantation ◽

T Cell ◽

Kidney Transplant ◽

Viral Infections ◽

Antiviral Treatment ◽

Bk Virus ◽

Cell Mediated Immunity ◽

Hematopoietic Stem ◽

Cell Immunity

Cytomegalovirus (CMV) and BK virus (BKV) are common viral infections after kidney transplant. Their negative impact on patient and graft outcomes have been well described. However, despite improvement in screening and prophylaxis strategies, CMV and BKV continue to negatively affect both short- and long-term graft survival. Adequate cell-mediated immunity is essential for the control and prevention of opportunistic viral infections, such as CMV and BK. Therefore, immune reconstitution, in particular, T-cell recovery, is a key factor in antiviral control following kidney transplantation. Cell-based immunotherapy offers an attractive alternative approach to traditional interventions. Adoptive T-cell transfer, via infusions of allogeneic virus-specific T lymphocytes (VST) is capable of restoring virus-specific T cell immunity and are safe and effective in the treatment of viral infections after hematopoietic stem cell transplantation. In this article, we review the emerging role of VST in the management of CMV and BKV after kidney transplantation. Based on the currently available data, VST may be a promising addition to the antiviral treatment armamentarium after kidney transplantation. Future studies are needed to more clearly define efficacy and risks of VST in the kidney transplant population.

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Lack of CD4+ T Cells Does Not Affect Induction of CD8+ T-Cell Immunity against Encephalitozoon cuniculi Infection

Infection and Immunity ◽

10.1128/iai.68.11.6223-6232.2000 ◽

2000 ◽

Vol 68 (11) ◽

pp. 6223-6232 ◽

Cited By ~ 39

Author(s):

Magali Moretto ◽

Lori Casciotti ◽

Brigit Durell ◽

Imtiaz A. Khan

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

T Cell Response ◽

T Cell Immunity ◽

Cell Mediated Immunity ◽

Wild Type ◽

Encephalitozoon Cuniculi ◽

Cell Immunity ◽

Mouse Tissues

ABSTRACT Cell-mediated immunity has been reported to play an important role in defense against Encephalitozoon cuniculi infection. Previous studies from our laboratory have underlined the importance of cytotoxic CD8+ T lymphocytes (CTL) in survival of mice infected with E. cuniculi. In the present study, immune response against E. cuniculi infection in CD4+T-cell-deficient mice was evaluated. Similar to resistant wild-type animals, CD4−/− mice were able to resolve E. cuniculi infection even at a very high challenge dose (5 × 107 spores/mouse). Tissues from infected CD4−/− mice did not exhibit higher parasite loads in comparison to the parental wild-type mice. Conversely, at day 21 postinfection, susceptible CD8−/− mice had 1014 times more parasites in the liver compared to control wild-type mice. Induction of the CD8+ T-cell response in CD4−/− mice against E. cuniculi infection was studied. Interestingly, a normal antigen-specific CD8+T-cell response to E. cuniculi infection was observed in CD4−/− mice (precursor proliferation frequency, 1/2.5 × 104 versus 1/104 in wild-type controls). Lack of CD4+ T cells did not alter the magnitude of the antigen-specific CTL response (precursor CTL frequency; 1/1.4 × 104 in CD4−/− mice versus 1/3 × 104 in control mice). Adoptive transfer of immune CD8+ T cells from both CD4−/− and wild-type animals prevented the mortality in CD8−/− mice.E. cuniculi infection thus offers an example of an intracellular parasitic infection where CD8+ T-cell immunity can be induced in the absence of CD4+ T cells.

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Alloantigen-activated (AAA) CD4+ T cells reinvigorate host endogenous T cell immunity to eliminate pre-established tumors in mice

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02102-6 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Kazuhiro Mochizuki ◽

Shogo Kobayashi ◽

Nobuhisa Takahashi ◽

Kotaro Sugimoto ◽

Hideki Sano ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Antitumor Immunity ◽

Unmet Need ◽

T Cell Response ◽

Hematopoietic Stem ◽

Cell Immunity ◽

Allogeneic Lymphocytes

Abstract Background Cancer vaccines that induce endogenous antitumor immunity represent an ideal strategy to overcome intractable cancers. However, doing this against a pre-established cancer using autologous immune cells has proven to be challenging. “Allogeneic effects” refers to the induction of an endogenous immune response upon adoptive transfer of allogeneic lymphocytes without utilizing hematopoietic stem cell transplantation. While allogeneic lymphocytes have a potent ability to activate host immunity as a cell adjuvant, novel strategies that can activate endogenous antitumor activity in cancer patients remain an unmet need. In this study, we established a new method to destroy pre-developed tumors and confer potent antitumor immunity in mice using alloantigen-activated CD4+ (named AAA-CD4+) T cells. Methods AAA-CD4+ T cells were generated from CD4+ T cells isolated from BALB/c mice in cultures with dendritic cells (DCs) induced from C57BL/6 (B6) mice. In this culture, allogeneic CD4+ T cells that recognize and react to B6 mouse-derived alloantigens are preferentially activated. These AAA-CD4+ T cells were directly injected into the pre-established melanoma in B6 mice to assess their ability to elicit antitumor immunity in vivo. Results Upon intratumoral injection, these AAA-CD4+ T cells underwent a dramatic expansion in the tumor and secreted high levels of IFN-γ and IL-2. This was accompanied by markedly increased infiltration of host-derived CD8+ T cells, CD4+ T cells, natural killer (NK) cells, DCs, and type-1 like macrophages. Selective depletion of host CD8+ T cells, rather than NK cells, abrogated this therapeutic effect. Thus, intratumoral administration of AAA-CD4+ T cells results in a robust endogenous CD8+ T cell response that destroys pre-established melanoma. This locally induced antitumor immunity elicited systemic protection to eliminate tumors at distal sites, persisted over 6 months in vivo, and protected the animals from tumor re-challenge. Notably, the injected AAA-CD4+ T cells disappeared within 7 days and caused no adverse reactions. Conclusions Our findings indicate that AAA-CD4+ T cells reinvigorate endogenous cytotoxic T cells to eradicate pre-established melanoma and induce long-term protective antitumor immunity. This approach can be immediately applied to patients with advanced melanoma and may have broad implications in the treatment of other types of solid tumors.

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T Cell-Mediated Control of HCMV Infection in Pediatric Patients Receiving Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v104.11.5087.5087 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5087-5087

Author(s):

Franco Locatelli ◽

Daniele Lilleri ◽

Laura Lozza ◽

Giovanna Giorgiani ◽

Piero De Stefano ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Count ◽

Hcmv Infection ◽

Cd8 T Cell ◽

T Cell Response ◽

Lymphoproliferative Response ◽

Hematopoietic Stem ◽

Cell Immunity

Abstract We are studying the development of HCMV-specific CD4+ and CD8+ T cell response after allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients. A new technique was developed to simultaneously detect HCMV-specific CD4+ and CD8+ effector T cells using HCMV-infected autologous dendritic cells as stimulators and intracellular staining of IFN-γ production by T cells. This prospective study is based on monthly determination of both HCMV-specific T cell number and in vitro lymphoproliferative response to crude HCMV antigen. Patients are routinely monitored for HCMV infection/reactivation in blood (by determination of either antigenemia or quantitation of viral DNA) and treated according to a strategy of pre-emptive therapy. So far, of 41 patients receiving HSCT from an HLA-identical related donor (n=18), unrelated donor (n=15) or a T cell-depleted HSCT from a haploidentical relative (n=8), 25 patients have reached day +180, while 16 patients completed a follow-up of 90 days. Among the 28 HCMV-seropositive HSCT recipients, 25 developed HCMV-specific CD4+ and CD8+ T-cell response within the first 60 days after transplantation. In these patients, absolute CD4+ T cell count increased over time, but remained lower than that of healthy controls also at later time points. By contrast, CD8+ T cells reached and maintained absolute levels comparable to those of controls already from day +60. At this time, HCMV-specific CD4+ T cell count was comparable to that of controls, while HCMV-specific CD8+ T cell count was higher than that of controls, with no significant change thereafter. On the other hand, in vitro lymphoproliferative response to HCMV antigen was detectable only in about one half of these patients, even at day +180. HCMV infection was detected in blood of 22 of the 25 patients in whom HCMV-specific T cells were present. It was either self-limiting (n=14) or in 8 patients required shorter ganciclovir course (median 7 days, range 5-14) than in the 3 HCMV seropositive patients who developed HCMV infection in the absence of specific immunity (median 67 days, range 42–82, p<0.001). No patient developed HCMV disease or late viral infections. Conversely, HCMV-specific response was detected in only 3/13 HCMV seronegative recipients (none of whom developing detectable HCMV infection in blood). In these patients, both absolute and HCMV-specific T cell counts were lower than those of both controls and HCMV-seropositive HSCT recipients. Our data suggest that effective HCMV-specific T cell immunity can promptly develop after HSCT (regardless of donor type or T-cell depletion of the graft), particularly in seropositive recipients in whom latent virus may be a major antigenic drive for rapid reconstitution of T cell compartment, especially of CD8+ lymphocytes. On the other hand, transfer of memory T cell immunity from seropositive donors to seronegative recipients does not appear to be always sufficient to permit detection of virus-specific lymphocytes in patient’s peripheral blood in the early period after the allograft, possibly also due to the lower chance of in vivo antigen stimulation. The frequent dissociation between IFN-γ production and lymphoproliferative response remains to be explained. Future studies could address modulation of antiviral intervention on the reconstitution of HCMV-specific T cell immune response.

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High prevalence of S. pyogenes Cas9-specific T cell sensitization within the adult human population – A balanced effector/regulatory T cell response

10.1101/295139 ◽

2018 ◽

Cited By ~ 3

Author(s):

Dimitrios L. Wagner ◽

Leila Amini ◽

Desiree J. Wendering ◽

Petra Reinke ◽

Hans-Dieter Volk ◽

...

Keyword(s):

Gene Therapy ◽

T Cells ◽

T Cell ◽

Cell Response ◽

Human Subjects ◽

T Cell Response ◽

Cell Mediated Immunity ◽

Healthy Human ◽

Cell Immunity

Summary ParagraphThe field of gene therapy has been galvanized by the discovery of the highly efficient and adaptable site-specific nuclease system CRISPR/Cas9 from bacteria.1,2 Immunity against therapeutic gene vectors or gene-modifying cargo nullifies the effect of a possible curative treatment and may pose significant safety issues.3-5 Immunocompetent mice treated with CRISPR/Cas9-encoding vectors exhibit humoral and cellular immune responses against the Cas9 protein, that impact the efficacy of treatment and can cause tissue damage.5,6 Most applications aim to temporarily express the Cas9 nuclease in or deliver the protein directly into the target cell. Thus, a putative humoral antibody response may be negligible.5 However, intracellular protein degradation processes lead to peptide presentation of Cas9 fragments on the cellular surface of gene-edited cells that may be recognized by T cells. While a primary T cell response could be prevented or delayed, a pre-existing memory would have major impact. Here, we show the presence of a ubiquitous memory/effector T cell response directed towards the most popular Cas9 homolog from Streptococcus pyogenes (SpCas9) within healthy human subjects. We have characterized SpCas9-reactive memory/effector T cells (TEFF) within the CD4/CD8 compartments for multi-effector potency and lineage determination. Intriguingly, SpCas9-specific regulatory T cells (TREG) profoundly contribute to the pre-existing SpCas9-directed T cell immunity. The frequency of SpCas9-reactive TREG cells inversely correlates with the magnitude of the respective TEFF response. SpCas9-specific TREG may be harnessed to ensure the success of SpCas9-mediated gene therapy by combating undesired TEFF response in vivo. Furthermore, the equilibrium of Cas9-specific TEFF and TREG cells may have greater importance in Streptococcus pyogenes-associated diseases. Our results shed light on the T cell mediated immunity towards the much-praised gene scissor SpCas9 and offer a possible solution to overcome the problem of pre-existing immunity.

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Is It Feasible to Use CMV-Specific T-Cell Adoptive Transfer as Treatment Against Infection in SOT Recipients?

Frontiers in Immunology ◽

10.3389/fimmu.2021.657144 ◽

2021 ◽

Vol 12 ◽

Author(s):

Estéfani García-Ríos ◽

Marcos Nuévalos ◽

Francisco J. Mancebo ◽

Pilar Pérez-Romero

Keyword(s):

T Cells ◽

T Cell ◽

Adoptive Transfer ◽

T Cell Response ◽

Cell Transplant ◽

Cmv Infection ◽

Hematopoietic Stem ◽

Cell Immunity ◽

Cell Adoptive Transfer ◽

The Impact

During the last decade, many studies have demonstrated the role of CMV specific T-cell immune response on controlling CMV replication and dissemination. In fact, it is well established that transplanted patients lacking CMV-specific T-cell immunity have an increased occurrence of CMV replication episodes and CMV-related complications. In this context, the use of adoptive transfer of CMV-specific T-cells has been widely investigated and applied to Hematopoietic Stem Cell Transplant patients and may be useful as a therapeutic alternative, to reconstitute the CMV specific T-cell response and to control CMV viremia in patients receiving a transplantation. However, only few authors have explored the use of T-cell adoptive transfer in SOT recipients. We propose a novel review in which we provide an overview of the impact of using CMV-specific T-cell adoptive transfer on the control of CMV infection in SOT recipients, the different approaches to stimulate, isolate and expand CMV-specific T-cells developed over the years and a discussion of the possible use of CMV adoptive cellular therapy in this SOT population. Given the timeliness and importance of this topic, we believe that such an analysis will provide important insights into CMV infection and its treatment/prevention.

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An epidemic Zika virus isolate suppresses antiviral immunity by disrupting antigen presentation pathways

Nature Communications ◽

10.1038/s41467-021-24340-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ryan D. Pardy ◽

Stefanie F. Valbon ◽

Brendan Cordeiro ◽

Connie M. Krawczyk ◽

Martin J. Richer

Keyword(s):

T Cell ◽

Zika Virus ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Cross Presentation ◽

Cell Immunity ◽

Asian Lineage ◽

Insight Into ◽

Host Tissues

AbstractZika virus (ZIKV) has emerged as an important global health threat, with the recently acquired capacity to cause severe neurological symptoms and to persist within host tissues. We previously demonstrated that an early Asian lineage ZIKV isolate induces a highly activated CD8 T cell response specific for an immunodominant epitope in the ZIKV envelope protein in wild-type mice. Here we show that a contemporary ZIKV isolate from the Brazilian outbreak severely limits CD8 T cell immunity in mice and blocks generation of the immunodominant CD8 T cell response. This is associated with a more sustained infection that is cleared between 7- and 14-days post-infection. Mechanistically, we demonstrate that infection with the Brazilian ZIKV isolate reduces the cross-presentation capacity of dendritic cells and fails to fully activate the immunoproteasome. Thus, our study provides an isolate-specific mechanism of host immune evasion by one Brazilian ZIKV isolate, which differs from the early Asian lineage isolate and provides potential insight into viral persistence associated with recent ZIKV outbreaks.

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T Lymphocyte Polyclonal Proliferation and Stress Response Style

Psychological Reports ◽

10.1177/0033294187060003-221.1 ◽

1987 ◽

Vol 60 (3_part_2) ◽

pp. 1121-1122

Author(s):

Edward A. Workman ◽

Mariano F. La Via

Keyword(s):

T Cell ◽

T Lymphocyte ◽

Life Stress ◽

Type A Behavior ◽

Response Style ◽

Cell Mediated Immunity ◽

Behavioral Indices ◽

Cell Immunity ◽

Stress Avoidance ◽

Pearson Correlations

18 subjects were measured on cell-mediated immunity (T lymphocyte polyclonal proliferation) and four behavioral indices including over-all life stress, stress-avoidance tendency, stress-intrusion tendency, and tendency toward cardiovascular Type A behavior. Of Pearson correlations computed between T lymphocyte polyclonal proliferation and each of the four behavioral indices, the only significant value was that, .47, between T cell immunity and tendency toward stress avoidance. Of the variables investigated, the best predictor of T cell immunocompetence is the tendency toward avoiding stress. Results are discussed in terms of implications for research.

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Mechanisms that allow vaccination against an oncolytic vesicular stomatitis virus-encoded transgene to enhance safety without abrogating oncolysis

Scientific Reports ◽

10.1038/s41598-021-94483-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Amanda W. K. AuYeung ◽

Robert C. Mould ◽

Ashley A. Stegelmeier ◽

Jacob P. van Vloten ◽

Khalil Karimi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Vesicular Stomatitis Virus ◽

Cell Response ◽

Viral Infections ◽

T Cell Response ◽

Oncolytic Viruses ◽

Oncolytic Virotherapy ◽

Cell Immunity ◽

Vesicular Stomatitis

AbstractVaccination can prevent viral infections via virus-specific T cells, among other mechanisms. A goal of oncolytic virotherapy is replication of oncolytic viruses (OVs) in tumors, so pre-existing T cell immunity against an OV-encoded transgene would seem counterproductive. We developed a treatment for melanomas by pre-vaccinating against an oncolytic vesicular stomatitis virus (VSV)-encoded tumor antigen. Surprisingly, when the VSV-vectored booster vaccine was administered at the peak of the primary effector T cell response, oncolysis was not abrogated. We sought to determine how oncolysis was retained during a robust T cell response against the VSV-encoded transgene product. A murine melanoma model was used to identify two mechanisms that enable this phenomenon. First, tumor-infiltrating T cells had reduced cytopathic potential due to immunosuppression. Second, virus-induced lymphopenia acutely removed virus-specific T cells from tumors. These mechanisms provide a window of opportunity for replication of oncolytic VSV and rationale for a paradigm change in oncolytic virotherapy, whereby immune responses could be intentionally induced against a VSV-encoded melanoma-associated antigen to improve safety without abrogating oncolysis.

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