KINETICS OF T CELL MEMORY RECOVERY IN LUNG TRANSPLANT RECIPIENTS TREATED WITH T CELL DEPLETION THERAPIES
C BentlejweskyA. ZeeviRobert J. KowalskyAlin GirnitaK. SpichtyJudith A. BritzKevin McDadeDavid GuaspariD. PostDiana ZaldonisKenneth R. McCurry
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P1014 Aims: A new therapeutic protocol consisting of pre-transplant (pre-Tx) T cell depletion (Thymoglobulin (Thy) or Campath prior to allograft revascularization) and minimal post-Tx immunosuppression was initiated in lung transplant recipients. This protocol is associated with a sharp decline of all T cell subsets immediate post treatment and the potential loss of T helper memory responses. Methods: In this study, we measured the recovery of T cell responses to ConA, CMV and EBV in a cohort of 41 lung transplant recipients (82 samples) followed for 3 months up to 18 months post-Tx. We also determined the T cell reactivity in a group of 11 normal volunteers. We used a new Cylex ImmuKnow-CD3 assay to assess T cell activity by ATP production. Results: 34 lung recipients were treated pre-Tx with Thy and 7 received Campath. The ConA responses post-Tx in the Thy group were significantly lower in lung recipients as compared to control subjects up to 10 months post-Tx: control ATP levels were 360+132 ng/ml (range 174-484 ng/ml) while in the Tx cohort the ATP levels were at 1-3 months 144+90 ng/ml, at 4-6 months 128+87 ng/ml and 7-9 months 144+45 ng/ml. The ConA responses seem to recover 10 months post-Tx. with a mean of 230+76 ng/ml at 10-12 months and 275+136 ng/ml > 12 months post-Tx. For CMV reactivity, we analyzed the results based on the CMV serological status of the recipients. In CMV negative recipients who were Tx with a CMV positive donor (R-/D+), the mean ATP level was 5+2 ng/ml (n=8) which was considered negative based on the observation in CMV negative controls (ATP<10ng/ml). In contrast, the CMV seropositive recipients (R+) had a mean ATP level of 20+24 ng/ml and 7/10 samples exhibited ATP levels >10 ng/ml. After 7 months post –Tx, the CMV-specific memory responses seem to recover in both groups; 13/15 patients in the R-/D+ exhibited an ATP response >10 ng/ml (mean 32+25 ng/ml) and 21/21 samples in R+ recipients had ATP >10 (mean 39+36ng/ml). The R-D- group had negative responses during the entire period (n=8, mean 5+3 ng/ml ATP). In control samples, the ATP levels were 125+93 ng/ml (range 22-262). For EBV-specific T cell memory, results greater than 15 ng/ml ATP were considered positive. Most of the recipients were EBV positive and the responses in the first 6 months post-Tx were suppressed (mean 29-20, with 8/19 expressing levels <15 ng/ml). Following 6 months post-Tx, only 4/44 samples exhibited levels of ATP <15 (mean 80+82, n=44). Similar results were seen with Campath treated patients although the number of samples was smaller and the patients had a shorter follow-up (less than 6 months). Conclusions: We have evaluated the ImmuKnow CD3-assay to monitor the functional recovery of T cell immunity to various pathogens following T cell depletion therapy. The CD3 assay may be used as adjunct to the assessment of viral load to monitor T cell immunity. This would allow for adjusting immunosuppression in Tx recipients to prevent rejection and to avoid infection.Keywords:
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Post-transplant immunosuppression almost always includes a combination of drugs and approaches based on a patient's individual situation, organ transplanted, and current developments in the field. Depending on these factors, approaches could include Induction immunosuppression, Maintenance immunosuppression, or Anti-rejection immunosuppression.
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For children with liver transplants (LT), achieving an "ideal outcome" is a balancing act: too little immunosuppression begets graft injury; too much begets systemic complications. We aimed to delineate the parental perspective on this tightrope.Parents of children with LT completed an internet-based survey about their child's immunosuppression.Children of respondents (n = 82) were a median 4 years from primary LT (range 0-22); 73% were on immunosuppression monotherapy. Parents' top concerns were related to immunosuppression complications; 46% were more concerned about immunosuppression complications than rejection; only 17% were more concerned about rejection than immunosuppression complications. Among parents of children on immunosuppression monotherapy, 29% still worried more about immunosuppression complications than rejection, 48% expressed equal concern for both. Time since LT (0-4 vs. >4 years) was not associated with concern level for rejection or immunosuppression complications. Caregivers were significantly more certain that their child's immunosuppression regimen was correct to prevent rejection than to mitigate complications (p < .005).Caregivers of children with LTs reported higher levels of concern and uncertainty about immunosuppression complications than rejection risk. Understanding parent and patient perspectives on IS, and incorporating them into immunosuppression counseling and decision-making, is critical to achieving truly "ideal" long-term outcomes.
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(1) Immunosuppression is responsible for excellent patient outcomes. (2) Immunosuppression withdrawal fails in most patients. (3) Patients who may benefit from immunosuppression withdrawal cannot currently be identified. (4) No data suggest that immunosuppression withdrawal decreases patient morbidity (ie, nephrotoxicity). (5) The minimization of immunosuppression instead of withdrawal may be adequate for improving patient outcomes.
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This chapter explains the evolution of haemodialysis (HD), peritoneal dialysis (PD), and transplantation. HD, as a routine treatment for renal failure, was initiated in the 1960s, followed by continuous ambulatory PD in the late 1970s. The recognition of the need for immunosuppression in transplantation in the 1960s enabled it to become the preferred treatment for many patients. Kidney transplantation as a therapeutic and practical option for renal replacement therapy was first reported in published literature at the turn of the twentieth century. The first known attempts at renal transplantation on humans were made without immunosuppression between 1906 and 1923 using pig, sheep, goat, and subhuman primate donors. These first efforts were conducted in France and Germany but others followed. The recognition of the need for immunosuppression in transplantation in the 1960s enabled it to become the preferred treatment for many patients.
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We developed an ex vivo lung CT (EVL-CT) technique that allows us to obtain detailed CT images and morphologically assess the retrieved lung from a donor for transplantation. After we recovered the lung graft from a brain-dead donor, we transported it to our hospital and CT images were obtained ex vivo before lung transplant surgery. The objective of this study was to investigate the correlation between the EVL-CT findings and post-transplant outcome in patients who underwent bilateral lung transplantation (BLT) or single lung transplantation (SLT).We retrospectively reviewed the records of 70 patients with available EVL-CT data who underwent BLT (34 cases) or SLT (36 cases) in our hospital between October 2007 and September 2017. The recipients were divided into 2 groups (control group, infiltration group) according to the findings of EVL-CT of the lung graft in BLT and SLT, respectively. Recipients in the control group were transplanted lung grafts without any infiltrates (BLT control group, SLT control group). Recipients in the infiltration group received lung grafts with infiltrates (BLT infiltration group, SLT infiltration group).The recipients in the BLT infiltration group showed significantly slower recovery from primary graft dysfunction and a longer mechanical ventilation period and ICU stay period than those in the BLT control group. The mechanical ventilation period was significantly longer in the recipients in the SLT infiltration group than those in the SLT control group.EVL-CT may predict the outcome of the early phase after lung transplantation.
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Purpese: Lung transplantation is now accepted as an effective therapy for end-stage pulmonary vascular and parenchymal diseases. Rejection is a major impediment to long-term survival of lung transplant recipients. Lung allograft rejection has been studied in various animal models. To study the immunological mechanism of its rejection the studies on lung allograft rejection must be performed in inbred animals such as mice or rats, However, it is very delicate and difficult to transplant the lung in small inbred animals, especially in mice. The technical difficulty hampered the investigations of lung allograft rejection. Methods: This study introduced the new lung transplantation technique in mice for immunological study, subcutaneous lung tissue transplantation, in which the piece of lung tissue with 1-1.5 mm thickness was introduced subcutaneously through incision site on flank and transplanted to subcutaneous site of shoulder of mouse. Histological changes were followed up in transplanted lung tissues for 18 to 21 days. Lung tissues from CBA mice or Balb/c mice were subcutaneously transplanted to Balb/c mice in experimental or control group respectively. Results: Histological changes in the grafts of experimental groups could be divided into 4 phases, inflammatory, immunological, necrotic and fibrotic phase, Immunological or necrotic phase in this study correlated with grade 1-3 or grade 3-4 of acute lung rejection classified by the Lung Rejection Study Group. Conclusion: It is concluded that the subcutaneous lung tissue transplantation can be a technique for immunological study on acute lung allograft rejection in mice.
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Lung transplantation is a definitive treatment option for select end-stage lung disease patients. Post lung transplantation, immunosuppression plays a significant role in a successful outcome. Rejection and infection are commonly encountered where immunosuppression plays an important role. Many immunosuppressive strategies have been designed and their protocols might vary from center to center. This review will focus on these perspectives as well as emerging perspectives during COVID times.
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Tonelli AR, Timofte I, Minai OA, Baz M, Akindipe O. Pulmonary hypertension before first and second lung transplantation. Abstract: Background: Pulmonary hypertension (PH) is frequently encountered in patients with advanced lung disease before the first and second lung transplantation. We sought to determine whether there is any relationship between pulmonary hemodynamics obtained before first and second lung transplantation. We also assessed whether PH has prognostic implications in lung transplant patients going for second transplantation. Methods: We included consecutive adult (16‐yr‐old or older) patients who underwent lung re‐transplantation, between 1997 and 2009, and had right heart catheterization before their first and second lung transplantation. Results: Eighteen patients were included in the study. Age at first transplantation was 50.4 (SD 10.4) yr, and bronchiolitis obliterans syndrome (BOS) in the transplanted lung was the only indication for re‐transplantation. PH was observed in 39% of the patients before the first lung transplant and in 56% of the subjects before re‐transplantation (p = 0.91). Pre‐capillary PH was present in 28% (n = 5) and 33% (n = 6) of the patients before first and second lung transplantation, respectively. None of the hemodynamic variables obtained before the first transplant predicted the development of PH before re‐transplantation. PH before re‐transplantation did not predict survival or development of BOS after re‐transplantation. Conclusions: PH before initial lung transplantation did not predict the development of PH before the second transplantation. In our cohort, PH before second lung transplantation did not predict outcomes after re‐transplantation.
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