Evolution of the Enzyme-Linked Immunosorbent Spot Assay for Post-Transplant Alloreactivity as a Potentially Useful Immune Monitoring Tool

Gebauer, Britta S.; Hricik, Donald E.; Atallah, Aymen; Bryan, Kathryn J.; Riley, Jocelyn; Tary‐Lehmann, Magdalena; Greenspan, Neil S.; Dejelo, Cora; Boehm, Bernhard O.; Hering, Bernhard J.; Heeger, Peter S.

doi:10.1034/j.1600-6143.2002.20908.x

Cited by 118 publications

(91 citation statements)

References 24 publications

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“…In addition, the assay has been optimized for use of frozen cells that can be easily stored. Although no studies to date have reported the use of this assay to identify functionally tolerant humans after transplantation, the frequency of IFN-␥-producing cells has been reported to correlate with the incidence of acute and chronic rejection as well as allograft function after renal transplantation (45)(46)(47). Obtaining and storing sufficient numbers of donor cells to perform the assay repeatedly is a practical limitation, particularly in recipients of deceased-donor organs.…”

Section: Elispot Assaymentioning

confidence: 99%

How Can We Measure Immunologic Tolerance in Humans?

Najafian

Albin²,

Newell³

2006

Journal of the American Society of Nephrology

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Prevention and treatment of allograft rejection in organ transplant recipients relies primarily on non-antigen-specific immunosuppression, with all its associated potential hazards and costs. Currently, the status of the recipient immune response is measured by monitoring pharmacologic drug levels and clinical/pathologic evaluation of graft function. Development of reliable assays that can measure accurately the status of the immune response not only would help clinicians customize the prescription of immunosuppressive drugs in individual patients but also may allow their complete withdrawal in some patients with immunologic tolerance. Furthermore, these assays would facilitate the safe evaluation of novel tolerogenic regimens. Achieving this goal has proved to be very difficult because it requires both a more in-depth understanding of complex mechanisms of tolerance and also identification of transplant patients with acquired tolerance to an allograft that can be studied. This review discusses the current understanding of tolerance mechanisms and outlines the unique and specific challenges in development of tolerance/monitoring assays in the field of transplantation. In addition, several of the most promising candidate assays are discussed in detail.

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Section: Elispot Assaymentioning

confidence: 99%

How Can We Measure Immunologic Tolerance in Humans?

Najafian

Albin²,

Newell³

2006

Journal of the American Society of Nephrology

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“…Indeed, CTLs that make other cytokines are viewed as unusual, and IFN-␥ production has often been used to enumerate antigen-specific CTLs. 58,59 IL-12 is a key cytokine for CTL differentiation from resting CD8 ϩ T cells. 56 As discussed above, the ability of IL-12 and IL-18 to promote the antigen-driven development of T H 1 immunity is well established.…”

Section: Ccr7mentioning

confidence: 99%

Interferon-γ Axis in Graft Arteriosclerosis

Tellides

Pober

2007

Circulation Research

107

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Abstract-Cardiac transplantation is the most effective treatment for advanced heart failure. Despite improvements in immunosuppression therapy that prevent acute rejection, cardiac allografts fail at rates of 3% to 5% per posttransplant year. The hallmark morphological lesion of chronically failing cardiac allografts, also seen in chronic renal and liver graft failure, is luminal stenosis of blood vessels, especially of conduit arteries. Late graft failure results from widespread secondary ischemic injury to the graft parenchyma rather than direct immune-mediated damage. Although this process affects the entire graft vasculature, graft arteriosclerosis is a suitable term to describe the problem because it applies to different types of failing organs and because it emphasizes the central feature, namely an accelerated form of arterial injury and remodeling. The precise pathogenesis of graft arteriosclerosis is unknown. In this review, we make the case that the signature T-helper type 1 cytokine, interferon (IFN)-␥, is a key effector in graft arteriosclerosis, which, together with the IFN-␥-inducing cytokine interleukin-12 and IFN-␥-inducible chemokines such as CXCR3 ligands, constitute a positive feedback loop for T-cell activation, differentiation, and recruitment that we refer to as the IFN-␥ axis. We evaluate the evidence to support this hypothesis in clinical observational and experimental animal studies. Additionally, we examine the regulation of IFN-␥ production within the artery wall, the effects of IFN-␥ on vessel wall cells, and the outcome of therapeutic agents on IFN-␥ production and signaling. These observations lead us to suggest that new therapies for graft arteriosclerosis should be optimized which focus on reducing IFN-␥ synthesis or actions. (Circ Res. 2007;100:622-632.)

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“…IFN-␥ and IL-10 ELISPOT assays were performed as described previously in detail (36,37). Briefly, 3 ϫ 10 5 responder and irradiated (40 Gy) stimulator cells were placed in triplicate wells.…”

Section: Elispot Assaymentioning

confidence: 99%

Achieving Donor-Specific Hyporesponsiveness Is Associated with FOXP3+ Regulatory T Cell Recruitment in Human Renal Allograft Infiltrates

Bestard¹,

Cruzado²,

Mestre³

et al. 2007

The Journal of Immunology

146

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Exploring new immunosuppressive strategies inducing donor-specific hyporesponsiveness is an important challenge in transplantation. For this purpose, a careful immune monitoring and graft histology assessment is mandatory. Here, we report the results of a pilot study conducted in twenty renal transplant recipients, analyzing the immunomodulatory effects of a protocol based on induction therapy with rabbit anti-thymocyte globulin low doses, sirolimus, and mofetil mycophenolate. Evolution of donor-specific cellular and humoral alloimmune response, peripheral blood lymphocyte subsets and apoptosis was evaluated. Six-month protocol biopsies were performed to assess histological lesions and presence of FOXP3+ regulatory T cells (Tregs) in interstitial infiltrates. After transplantation, there was an early and transient apoptotic effect, mainly within the CD8+HLADR+ T cells, combined with a sustained enhancement of CD4+CD25+high lymphocytes in peripheral blood. The incidence of acute rejection was 35%, all steroid sensitive. Importantly, only pretransplant donor-specific cellular alloreactivity could discriminate patients at risk to develop acute rejection. Two thirds of the patients became donor-specific hyporesponders at 6 and 24 mo, and the achievement of this immunologic state was not abrogated by prior acute rejection episodes. Remarkably, donor-specific hyporesponders had the better renal function and less chronic renal damage. Donor-specific hyporesponsiveness was inhibited by depleting CD4+CD25+high T cells, which showed donor-Ag specificity. FOXP3+CD4+CD25+high Tregs both in peripheral blood and in renal infiltrates were higher in donor-specific hyporesponders than in nonhyporesponders, suggesting that the recruitment of Tregs in the allograft plays an important role for renal acceptance. In conclusion, reaching donor-specific hyporesponsiveness is feasible after renal transplantation and associated with Treg recruitment in the graft.

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Evolution of the Enzyme-Linked Immunosorbent Spot Assay for Post-Transplant Alloreactivity as a Potentially Useful Immune Monitoring Tool

Cited by 118 publications

References 24 publications

How Can We Measure Immunologic Tolerance in Humans?

How Can We Measure Immunologic Tolerance in Humans?

Interferon-γ Axis in Graft Arteriosclerosis

Achieving Donor-Specific Hyporesponsiveness Is Associated with FOXP3+ Regulatory T Cell Recruitment in Human Renal Allograft Infiltrates

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