Donor non-specific IFN-γ production by primed alloreactive cells as a potential screening test to predict the alloimmune response

Bendjelloul, Farid; Desin, Taseen S.; Shoker, Ahmed

doi:10.1016/j.trim.2003.08.003

Cited by 16 publications

(9 citation statements)

References 35 publications

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“…40 Interestingly, IFN-␥ producing alloreactive T cells are detectable in hosts that have never been exposed to alloantigen, and the activation of these cells has been attributed to cross-reactivity to environmental antigens, including viral and bacterial infections. [41][42][43][44] Importantly, the presence of IFN-␥-producing alloreactive T cells has been shown to correlate with the rejection of allogeneic tissues, 14,16,45,46 but in these studies, the frequency of naive alloreactive T cells could not be determined. Our results demonstrate that TNF-␣ production by activated alloreactive T cells also correlates with the rejection of allogeneic tissues and has the additional advantage of identifying naive alloreactive T cells that would be overlooked in studies evaluating only IFN-␥ production.…”

Section: Discussionmentioning

confidence: 94%

Rapid quantification of naive alloreactive T cells by TNF-α production and correlation with allograft rejection in mice

Brehm¹,

Mangada

Markees

et al. 2006

Blood

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Allograft transplantation requires chronic immunosuppression, but there is no effective strategy to evaluate the long-term maintenance of immunosuppression other than assessment of graft function. The ability to monitor naive alloreactive T cells would provide an alternative guide for drug therapy at early, preclinical stages of graft rejection and for evaluating tolerance-inducing protocols. To detect and quantify naive alloreactive T cells directly ex vivo, we used the unique ability of naive T cells to rapidly produce TNF-␣ but not IFN-␥. Naive alloreactive T cells were identified by the production of TNF-␣ after a 5-hour in vitro stimulation with alloantigen and were distinguished from effector/memory alloreactive T cells by the inability to produce IFN-␥. Moreover, naive alloreactive T cells were not detected in mice tolerized against specific alloantigens. The frequency of TNF-␣-producing cells was predictive for rejection in an in vivo cytotoxicity assay and correlated with skin allograft rejection. Naive alloreactive T cells were also detected in humans, suggesting clinical relevance. We conclude that rapid production of TNF-␣ can be used to quantify naive alloreactive T cells, that it is abrogated after the induction of tolerance, and that it is a potential tool to predict allograft rejection. IntroductionThe ability to reject allografts is a hallmark of the immune system and is mediated by the vigorous immune response generated against MHC-disparate haplotypes. To prevent allograft rejection in patients undergoing transplantation, chronic immunosuppressive drug therapy is required. [1][2][3] Clinical parameters of graft function currently guide drug choice and dosage during immunosuppressive therapy, but significant organ damage can occur prior to recognition of ongoing but subclinical graft rejection. The ability to identify and quantify alloreactive T cells prior to the appearance of clinical signs of graft rejection could improve patient management or the use of immunosuppressive drugs for maintaining allograft survival. A protocol to rapidly quantify naive and effector/memory alloreactive T cells could also be used to evaluate tolerance induction protocols as they enter clinical transplantation trials. [4][5][6] T cells are an important component of allograft rejection, and alloreactive T cells represent a substantial proportion of the naive T-cell repertoire. Between 0.1% and 10% of naive T cells within an individual are estimated to be reactive with any unique allogeneic MHC haplotype. [7][8][9][10] Assays that have been used to quantify alloreactive T cells, including limiting dilution analysis, 11,12 enzymelinked immunospot assays, [13][14][15][16] and in vivo proliferation assays, 10,13,15,17 require an extended in vitro culture period. However, these assays have not been translated effectively into the clinic and do not permit direct and rapid identification of naive alloreactive T cells.Naive T cells are thought to acquire full functionality only after a programmed pathway of differentiatio...

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Section: Discussionmentioning

confidence: 94%

Rapid quantification of naive alloreactive T cells by TNF-α production and correlation with allograft rejection in mice

Brehm¹,

Mangada

Markees

et al. 2006

Blood

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“…At present, this preexisting donor‐specific cellular immunity is not routinely assessed pretransplant . Methods such as proliferation, limiting dilution, and enzyme‐linked immunospot (ELISPOT) assays may be used to detect preformed cellular alloreactivity, but require cell isolation and prolonged incubation times . In this study, we have used a flow‐cytometric assay to simultaneously quantify and characterize alloreactive CD4 + and CD8 + T cells directly after stimulation of 6 h. The procedure previously developed for isolated PBMCs was now further advanced to be used directly from whole blood with small sample volumes.…”

Section: Introductionmentioning

confidence: 99%

Donor‐specific alloreactive T cells can be quantified from whole blood, and may predict cellular rejection after renal transplantation

Fischer

Leyking

Schäfer³

et al. 2017

Eur J Immunol

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Preformed cellular alloreactivity can exist prior to transplantation and may contribute to rejection. Here, we used a rapid flow-cytometric whole-blood assay to characterize the extent of alloreactive T cells among 1491 stimulatory reactions from 61 renal transplant candidates and 75 controls. The role of preformed donor-specific alloreactive T cells in cellular rejection was prospectively analyzed in 21 renal transplant recipients. Alloreactive CD8 T cells were more frequent than respective CD4 T cells, and these levels were stable over time. CD8 T cells were effector-memory T cells largely negative for expression of CD27, CD62L, and CCR7, and were susceptible to steroid and calcineurin inhibitor inhibition. Alloreactivity was more frequent in samples with higher number of HLA mismatches. Moreover, the percentage of individuals with alloreactive T cells was higher in transplant candidates than in controls. Among transplant candidates, 5/61 exhibited alloreactive CD8 T cells against most stimulators, 23/61 toward a limited number of stimulators, and 33/61 did not show any alloreactivity. Among 21 renal transplant recipients followed prospectively, one had donor-specific preformed T-cell alloreactivity. She was the only patient who developed cellular rejection posttransplantation. In conclusion, donor-specific alloreactive T cells may be rapidly quantified from whole blood, and may predict cellular rejection after transplantation.

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“…The capacity of virus-specific memory T cells to cross-react with HLA alloantigens is facilitated by the T cell receptor (TCR), which has been shown to mediate immunological responses in individuals otherwise considered to have been “naïve” to allogeneic stimulation, thereby accounting for the presence of alloreactive memory T cells in individuals with no prior sensitization [6]–[9]. Importantly, cross-reactive anti-viral memory T cells are likely to be less susceptible to immunosuppression regimens and may exponentially expand in the setting of specific viral reactivation.…”

Section: Introductionmentioning

confidence: 99%

Cross-Reactive Anti-Viral T Cells Increase Prior to an Episode of Viral Reactivation Post Human Lung Transplantation

et al. 2013

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Human Cytomegalovirus (CMV) reactivation continues to influence lung transplant outcomes. Cross-reactivity of anti-viral memory T cells against donor human leukocyte antigens (HLA) may be a contributing factor. We identified cross-reactive HLA-A*02:01-restricted CMV-specific cytotoxic T lymphocytes (CTL) co-recognizing the NLVPMVATV (NLV) epitope and HLA-B27. NLV-specific CD8+ T cells were expanded for 13 days from 14 HLA-A*02:01/CMV seropositive healthy donors and 11 lung transplant recipients (LTR) then assessed for the production of IFN-γ and CD107a expression in response to 19 cell lines expressing either single HLA-A or -B class I molecules. In one healthy individual, we observed functional and proliferative cross-reactivity in response to B*27:05 alloantigen, representing approximately 5% of the NLV-specific CTL population. Similar patterns were also observed in one LTR receiving a B27 allograft, revealing that the cross-reactive NLV-specific CTL gradually increased (days 13–193 post-transplant) before a CMV reactivation event (day 270) and reduced to basal levels following viral clearance (day 909). Lung function remained stable with no acute rejection episodes being reported up to 3 years post-transplant. Individualized immunological monitoring of cross-reactive anti-viral T cells will provide further insights into their effects on the allograft and an opportunity to predict sub-clinical CMV reactivation events and immunopathological complications.

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Donor non-specific IFN-γ production by primed alloreactive cells as a potential screening test to predict the alloimmune response

Cited by 16 publications

References 35 publications

Rapid quantification of naive alloreactive T cells by TNF-α production and correlation with allograft rejection in mice

Rapid quantification of naive alloreactive T cells by TNF-α production and correlation with allograft rejection in mice

Donor‐specific alloreactive T cells can be quantified from whole blood, and may predict cellular rejection after renal transplantation

Cross-Reactive Anti-Viral T Cells Increase Prior to an Episode of Viral Reactivation Post Human Lung Transplantation

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