Christopher Wigfield

Transfer of tolerance to collagen type v suppresses T-helper-cell-17 lymphocyte-mediated acute lung transplant rejection

Background. Rat lung allograft rejection is mediated by collagen type V (col(V)) specific T-helper-cell 17 (Th17) cells. Adoptive transfer of these cells is sufficient to induce rejection pathology in isografts, whereas tolerance to col(V) suppresses allograft rejection. Therefore, we tested whether regulatory T cells from tolerant rats could suppress the Th17-mediated rejection in the syngeneic model of lung transplantation. Methods. Rats were subjected to syngeneic left lung transplantation, and acute rejection was induced by adoptive transfer of lymph node cells from col(V)-immunized rats. Tolerance was induced by intravenous injection of col(V), and spleen lymphocytes were used for adoptive transfer. CD4+ T cells were depleted using magnetic beads. Lung isografts were analyzed using micro-positron emission tomography imaging and histochemistry. The transvivo delayed type hypersensitivity assay was used to analyze the Th17 response. Results. Adoptive cotransfer of col(V)-specific effector cells with cells from col(V)-tolerized rats suppressed severe vasculitis and bronchiolitis with parenchymal inflammation, and the expression of interleukin (IL)-17 transcripts in mediastinal lymph nodes induced by effector cells alone. Analysis by transvivo delayed type hypersensitivity showed that the reactivity to col(V) was dependent on the presence of tumor necrosis factor-&agr; and IL-17 but not interferon-&ggr;. Depletion of CD4+ T cells from the suppressor cell population abrogated the col(V)-specific protection. Conclusion. Th17-mediated acute rejection after lung transplantation is ameliorated by CD4+ col(V)-specific regulatory T cells. The mechanism for this Th17 suppression is consistent with tolerance induction to col(V). The goal of transplantation treatment, therefore, should target Th17 development and not suppression of T-cell activation by suppressing IL-2.

Donation after cardiac death lung transplantation outcomes.

Purpose of reviewLung transplantation is now a well established treatment option for several end-stage respiratory diseases. Survival after lung transplantation has significantly improved over the last decade. The primary limitation to increased utilization of lung transplantation remains donor scarcity. Suitable allografts have been procured from donors after determination of neurologic death and from donors after determination of cardiac death (DDCD or DCD). Historically, the first human lung transplantation performed, utilized an allograft procured after cardiovascular death, also referred to as nonheart-beating donor.The experience at University of Wisconsin in 1993 reintroduced DCD lung transplantation with the first successful clinical case. Recent findingsA potential additional lung allograft source, DCD lung transplantation has been established with very acceptable outcomes observed by several centers. We provide the relevant background for the rationale of donor allograft expansion to include DCD lungs from controlled (Maastricht category III donors). SummaryThis review considers the available evidence for DCD lung transplantation and compares reported primary graft dysfunction rates and current survival data available.

Cellular Basis of Tissue Regeneration by Omentum

The omentum is a sheet-like tissue attached to the greater curvature of the stomach and contains secondary lymphoid organs called milky spots. The omentum has been used for its healing potential for over 100 years by transposing the omental pedicle to injured organs (omental transposition), but the mechanism by which omentum helps the healing process of damaged tissues is not well understood. Omental transposition promotes expansion of pancreatic islets, hepatocytes, embryonic kidney, and neurons. Omental cells (OCs) can be activated by foreign bodies in vivo. Once activated, they become a rich source for growth factors and express pluripotent stem cell markers. Moreover, OCs become engrafted in injured tissues suggesting that they might function as stem cells. Omentum consists of a variety of phenotypically and functionally distinctive cells. To understand the mechanism of tissue repair support by the omentum in more detail, we analyzed the cell subsets derived from the omentum on immune and inflammatory responses. Our data demonstrate that the omentum contains at least two groups of cells that support tissue repair, immunomodulatory myeloid derived suppressor cells and omnipotent stem cells that are indistinguishable from mesenchymal stem cells. Based on these data, we propose that the omentum is a designated organ for tissue repair and healing in response to foreign invasion and tissue damage.

Donation after cardiac death for lung transplantation: a review of current clinical practice.

PURPOSE OF REVIEW This review presents a concise update on clinical donation after cardiac death (DCD or DDCD) lung transplantation. Lung allografts have predominantly been procured from donors after determination of neurologic death but will not meet the existing demand. A steadily increasing need for lungs is evident worldwide, especially in an era of improved outcomes for recipients. Other solid organ utilization from donors after determination of cardiac death has markedly increased internationally, but the utilization rate of lungs from such donors is still considerably less. The multifaceted reasons for this discrepancy are considered, and the recent evidence available supporting DCD for lung transplantation in clinical practice is presented in context. The recent experimental research studies are not within the remit of this appraisal. RECENT FINDINGS The more recent and markedly increased lung recipient cohorts showed very satisfactory survival outcomes for DCD transplantation in several programs. The overall utilization rate, however, remains low. The background and the rationale of lung donor allograft expansion to proactively include DCD allografts from controlled (Maastricht category III donors) is re-emphasized in this review. The feasibility of other DCD categories for lung transplantation is considered. This is particularly prudent with the advent of the ex-vivo lung perfusion modality in pulmonary procurement. SUMMARY Despite evidence for adequate survival outcomes and reported favorable primary graft dysfunction rates, DCD lung transplantation remains underutilized in most countries. Waiting times could be notably reduced and mortality of lung candidates arguably decreased by a more decided and appropriate implementation of proven DCD lung transplant strategies.

Role of innate immunity in primary graft dysfunction after lung transplantation.

Purpose of reviewPrimary graft dysfunction (PGD), a form of acute lung injury after lung transplantation, has a significant impact on clinical outcomes after lung transplantation. This potentially reversible graft impairment occurs after ischemia–reperfusion injury. This review describes the expanding body of literature evaluating the central role of innate immune activation, nonadaptive responses and dysregulation in the development of PGD after lung transplant. Recent findingsThe innate immune system, highlighted by Toll-like receptor pathways and neutrophil migration and influx, plays an important role in the initiation and propagation of ischemia–reperfusion injury. Recent plasma biomarker and gene association studies have identified several genes and proteins composing innate immune pathways to be associated with PGDs. Long pentraxin-3 and Toll-like receptors, as well as inflammasomes and Toll-interacting protein, are associated with the development of PGD after lung transplantation. SummaryInnate immune pathways are involved in the development of PGD and may provide attractive targets for therapies. It may be possible to prevent or treat PGD, as well as to allow pre-transplant PGD risk stratification. To improve understanding of the mechanisms behind clinical risk factors for PGD will require further in-depth correlation of donor-specific and recipient-related triggers of nonadaptive immune responses.

ISHLT Consensus Statement on adult and pediatric airway complications after lung transplantation: Definitions, grading system, and therapeutics

Airway complications remain a major cause of morbidity and mortality after cardiothoracic transplantation. The reported incidence of airway ischemic complications varies widely, contributed to by the lack of a universally accepted grading system and standardized definitions. Furthermore, the majority of the existing classification systems fail to integrate the wide range of possible bronchial complications that may develop after lung transplant. Hence, a Working Group was created by the International Society for Heart and Lung Transplantation with the aim of elaborating a universal definition of adult and pediatric airway complications and grading system. One such area of focus is to understand the problem in the context of a more standardized consensus of classifying airway ischemia. This consensus definition will have major clinical, therapeutics, and research implications.