Immune Regulation and Graft Survival in Kidney Transplant Recipients Are Both Enhanced by Human Leukocyte Antigen Matching

proyectos, Serrano Rodríguez, Daniel, especialista de; Jankowska‐Gan, Ewa; Haynes, Lynn D.; Leverson, Glenn; Munoz, Alejandro; Heisey, Dennis M.; Sollinger, Hans W.; Burlingham, William J.

doi:10.1111/j.1600-6143.2004.00385.x

Cited by 48 publications

(42 citation statements)

References 35 publications

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“…What is unclear is the complete immune mechanism resulting in graft dysfunction. The TV-DTH assay, which provides a readout of cell-mediated (T-cell dependent) immune memory (16,18,19) to col(V), may be only a surrogate marker of an underlying process that is humoral and complement mediated. Although there is likely a humoral component to col(V)-specific autoimmunity, the idea that graft dysfunction is due entirely to antibody-and complement-mediated pathways seems unlikely given the severe mononuclear cell infiltration in isografts placed in col(V)-immunized rats ( Figure 5B) and the fact that the C4d deposition was not detected in the damaged lungs (D.S.W., unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation

Bobadilla¹,

Love²,

Jankowska‐Gan³

et al. 2008

Am J Respir Crit Care Med

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Rationale: The pathogenesis of primary graft dysfunction (PGD), a serious complication of lung transplantation, is poorly understood. Human studies and rodent models have shown that collagen type V (col [V]), stimulates IL-17-dependent cellular immunity after lung transplantation. Objectives: To determine whether patients with end-stage lung disease develop pretransplant col(V)-specific cellular immunity, and if so, the impact of this response on PGD. Methods: Trans-vivo delayed-type hypersensitivity (TV-DTH) assays were used to evaluate memory T-cell responses to col(V) in 55 patients awaiting lung transplantation. Pa O 2 /FI O 2 index data were used to assess PGD. Univariate risk factor analysis was performed to identify variables associated with PGD. Rats immunized with col(V) or irrelevant antigen underwent lung isografting to determine if prior anti-col(V) immunity triggers PGD in the absence of alloreactivity. Measurements and Main Results: We found that 58.8% (10/17) of patients with idiopathic pulmonary fibrosis, and 15.8% (6/38) of patients without idiopathic pulmonary fibrosis tested while on the wait list for a lung transplant were col(V) DTH positive. Col(V) reactivity was CD4 + T-cell and monocyte mediated, and dependent on IL-17, IL-1b, and tumor necrosis factor (TNF)-a. Pa O 2 /FI O 2 indices were impaired significantly 6-72 hours after transplantation in col(V)-reactive versus nonreactive patients. Univariate risk factor analysis identified only preoperative TV-DTH to col(V) and ischemic time as predictors of PGD. Finally, in a rat lung isograft model, col(V) sensitization resulted in significantly lower Pa O 2 /FI O 2 , increased local TNF-a and IL-1b production, and a moderate-to-severe bronchiolitis/ vasculitis when compared with control isografts. Conclusions: The data suggest that activation of innate immunity by col(V)-specific Th-17 memory cells represents a novel pathway to PGD after lung transplantation.Keywords: lung transplantation; primary graft dysfunction; collagen type V; autoimmunity; memory T cellThe historic paradigm of allograft failure due primarily to humoral and cell-mediated immune responses to foreign major histocompatability complex (MHC) antigens has recently been challenged by additional hypotheses (1-3). Although it is clear that immunity to donor human leukocyte antigen (HLA) serves a significant role in mediating allograft rejection, recent evidence suggests that self-antigens exposed during ischemiareperfusion injury may, under some circumstances, present an equal, if not greater, barrier to graft acceptance (4-6). In lung transplantation, one such cryptic self-antigen is collagen type-V (col[V]) (2). Col(V) is classified as a minor fibrillar collagen and, in the human lung, the ratio of matrix collagens is 86:28:8:1.6 (for collagens I, III, IV, and V, respectively) (7). Under normal physiologic conditions, col(V) coassembles into heterotypic fibrils with the major fibrillar collagen type I (8, 9). In fact, the majority of the col(V) monomer is normally partitioned ...

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Section: Discussionmentioning

confidence: 99%

Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation

Bobadilla¹,

Love²,

Jankowska‐Gan³

et al. 2008

Am J Respir Crit Care Med

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“…As a result, organizations such as the national Organ Procurement and Transplantation Network in the United States only require typing for HLA-A, B and DR antigens [1]. However, it should not be forgotten that the better the matching of HLA antigens between donor and recipient the better the chance of survival of a given organ [2]. A major concern in the use of immunosuppressive drugs is the susceptibility to infections rendered to the transplant recipient due to the non-specific action of these agents.…”

Section: Introductionmentioning

confidence: 99%

MHC-Ig Dimers: The next Frontier in Transplantation Immunology

Wigina

Jeza

2015

Int Jour of Biomed Res

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Organ transplantation offers hope to a variety of patients with terminal functioning organs and tissues. This is currently made possible by administration of general immunosuppressive drugs. To date, inducing tolerance to allografts has become the holy grail of every transplantation immunologist. In effect, there has been a great deal of research aiming to come up with alternative therapeutic mechanisms that would allow one to do away with or reduce the amount of general immunosuppressive drugs used either at the induction, maintenance, or both phases. It has been shown in recent years that MHC-Ig dimers can induce suppression of alloresponsive T cells in a donor specific fashion. Consequently, MHC-Ig fusion proteins are currently forming the next field for exploitation which is great progress in transplantation immunology since the discovery of the first immunosuppressive drugs in terms of inducing tolerance to transplanted organs and tissues. This review aims to discuss this progress.

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“…Patient #8 exhibits the donor-sensitized pattern, characterized by a high response to donor antigen and no linked suppression. This response is associated with graft rejection in clinical case studies 8 .…”

Section: Evaluation Of Renal Transplant Recipients For Donor Antigen-mentioning

confidence: 99%

“…Bystander suppression of a DTH recall response in the presence of donor antigen is characteristic of transplant recipients with accepted allografts 2,[4][5][6][7][8][9][10][11][12][13][14] . The monitoring of transplant recipients for alloreactivity and regulation by Tv-DTH may identify a subset of patients who could benefit from reduction of immunosuppression without elevated risk of rejection or deteriorating renal function.…”

Section: Introductionmentioning

confidence: 99%

Trans-vivo Delayed Type Hypersensitivity Assay for Antigen Specific Regulation

Jankowska‐Gan

Hegde

Burlingham

2013

JoVE

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Delayed-type hypersensitivity response (DTH) is a rapid in vivo manifestation of T cell-dependent immune response to a foreign antigen (Ag) that the host immune system has experienced in the recent past. DTH reactions are often divided into a sensitization phase, referring to the initial antigen experience, and a challenge phase, which usually follows several days after sensitization. The lack of a delayed-type hypersensitivity response to a recall Ag demonstrated by skin testing is often regarded as an evidence of anergy. The traditional DTH assay has been effectively used in diagnosing many microbial infections.Despite sharing similar immune features such as lymphocyte infiltration, edema, and tissue necrosis, the direct DTH is not a feasible diagnostic technique in transplant patients because of the possibility of direct injection resulting in sensitization to donor antigens and graft loss. To avoid this problem, the human-to-mouse "trans-vivo" DTH assay was developed 1,2 . This test is essentially a transfer DTH assay, in which human peripheral blood mononuclear cells (PBMCs) and specific antigens were injected subcutaneously into the pinnae or footpad of a naïve mouse and DTH-like swelling is measured after 18-24 hr 3 . The antigen presentation by human antigen presenting cells such as macrophages or DCs to T cells in highly vascular mouse tissue triggers the inflammatory cascade and attracts mouse immune cells resulting in swelling responses. The response is antigen-specific and requires prior antigen sensitization. A positive donor-reactive DTH response in the Tv-DTH assay reflects that the transplant patient has developed a pro-inflammatory immune disposition toward graft alloantigens.The most important feature of this assay is that it can also be used to detect regulatory T cells, which cause bystander suppression. Bystander suppression of a DTH recall response in the presence of donor antigen is characteristic of transplant recipients with accepted allografts 2,[4][5][6][7][8][9][10][11][12][13][14] . The monitoring of transplant recipients for alloreactivity and regulation by Tv-DTH may identify a subset of patients who could benefit from reduction of immunosuppression without elevated risk of rejection or deteriorating renal function.A promising area is the application of the Tv-DTH assay in monitoring of autoimmunity 15,16 and also in tumor immunology 17 . Video LinkThe /injection. 4. If there is a noticeable red blood cell contamination, perform lysis of red cell using ACK lysis buffer after first wash. Remove ACK buffer by washing 2 times with PBS.

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Immune Regulation and Graft Survival in Kidney Transplant Recipients Are Both Enhanced by Human Leukocyte Antigen Matching

Cited by 48 publications

References 35 publications

Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation

Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation

MHC-Ig Dimers: The next Frontier in Transplantation Immunology

Trans-vivo Delayed Type Hypersensitivity Assay for Antigen Specific Regulation

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