- Email: [email protected]
Tocilizumab for Antibody-Mediated Rejection in the Setting of Cardiac Allograft Vasculopathy
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The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
baseline of 8.9 g/dL to 6.9 g/dL. He underwent push enteroscopy during this hospital stay which demonstrated bleeding jejunal angioplastic lesions. The PAP readings during the episodes of GI bleeding were reviewed. There was a significant reduction in PAP at the date of symptom onset from one day prior; from 57/26 mmHg (mPAP 38 mmHg) on 6/3 to 48/24 mmHg (mPAP 34 mmHg) on 6/4 corresponding with 2 g/dL drop in Hb level (See figure). This phenomenon was seen in a prior episode of GI bleeding 2 months prior. The PAP numbers dropped considerably to 39/18 mmHg (mPAP 27 mmHg) at the onset of symptoms compared with 49/22 mmHg (mPAP 33 mmHg) 1 day prior associated with 2.9 g/dL decline in Hb level. During the time PAP changes were observed, diuretic therapy was not modified. Summary: In patients implanted with CardioMEMS device, a sudden drop in PAP can herald a GI bleeding episode. Monitoring PAP trends can be helpful in LVAD patients who are at higher risk for GI bleeding.
69 Successful Bacteriophage Therapy for Treatment of MultidrugResistant Pseudomonas aeruginosa Infection in a Cystic Fibrosis Patient N. Law,1 C. Logan,1 C. Furr,2 S. Lehman,2 S. Morales,2 F. Rosas,2 A. Gaidamaka,2 I. Bilinsky,2 P. Grint,2 R. Schooley,1 and S. Aslam.1 1University of California, San Diego, San Diego, CA; and the 2 AmpliPhi Biosciences Inc, San Diego, CA.
68 Inverted Lung Transplantation: Interposition of Pericardial Conduit for Pulmonary Venous Anastomosis H. Yamamoto,1 K. Miyoshi,2 T. Kurosaki,1 S. Otani,1 M. Okazaki,1 S. Sugimoto,1 M. Yamane,1 S. Toyooka,1 and T. Oto.1 1General Thoracic Surgery, Organ Transplant Center, Okayama University Hospital, Okayama, Japan; and the 2General Thoracic Surgery, Okayama Medical Center, Okayama, Japan. Introduction: Lung transplantation (LTx) is still limited by a shortage of suitable donor lungs. Evolving flexible surgical procedures help increase the chances of LTx by unfolding recipient-to-donor matching options based on the pre-existing organ allocation concept. In particular, right single LTx using an inverted left donor lung may be considered under the following conditions: 1) Despite a right-side-predominant lung dysfunction in a recipient candidate, the option is limited to the use of a left single donor lung due to evidence of lung injury in the right donor lung or necessity to share the organ with another candidate prioritized on the waitlist; 2) Left side LTx in the recipient is impossible due to a past history in the recipient of thoracic surgery. One of the key challenges in performing inverted LTx is to adjust the positional relationship between the recipient’s and graft’s hilar structures. Herein, we report a case of successful left-to-right inverted LTx using interposition of a pericardial conduit for pulmonary venous anastomosis. Case Report: A left lung graft was offered to a 59-year-old male who had predominant damage of the right lung by idiopathic pulmonary fibrosis (Fig.1A). We decided to transplant the left donor lung into the right thorax of the recipient, considering his serious disease condition. Due to the anterior-posterior position gap, adjustment of the cuff length of the pulmonary artery and vein was required. Pulmonary artery anastomosis could be performed by leaving both the donor and recipient cuff long, but an extension of the pulmonary vein by interposition of a pericardial conduit was required for anastomosis (Fig.1B). The patient developed no anastomotic complications after the LTx. Summary: left-to-right inverted LTx is technically feasible by using an autologous pericardial conduit in selected cases. The technique has the potential benefit of encouraging exploration and expansion of unprecedented donor-recipient matching patterns in LTx.
Introduction: Bacteriophages are host-specific lytic viruses that are of increasing interest as adjunctive therapy for treatment of multi-drug resistant (MDR) pathogens. Case Report: We describe the use of bacteriophage therapy (BT) in a 26year-old cystic fibrosis (CF) patient awaiting lung transplantation who was admitted for respiratory failure requiring mechanical ventilation for 12 days. The hospital course was complicated by MDR Pseudomonas aeruginosa (PA) pneumonia, persistent respiratory failure, and colistin-induced renal failure (listed for concomitant kidney transplant). Due to worsening clinical status, BT was explored as an adjunct to antibiotics. The patient was approved under emergency IND#17710 by the FDA to receive AB-PA01 (combination of 4 lytic phages) active against the clinical PA isolates. This was given every 6 hours intravenously (IV) for 8 weeks. As noted in Figure 1, the patient was bed-bound due to severe dyspnea and required 30 L/min O2 via high flow nasal cannula (NC) at BT initiation. MDR PA pneumonia resolved by Day 7. Her respiratory status continued to improve and by end of therapy (EOT) she was on 4 L/min O2 via NC and was able to work with physical therapy. No adverse events related to BT occurred. There was no recurrent pneumonia or CF exacerbation within 90-days following the end of treatment. Renal failure resolved once off colistin and the patient was removed from the kidney transplant waitlist. Summary: We describe the successful use of BT in a CF patient awaiting lung transplant. Given the concern for MDR PA in CF patients, BT may offer a viable anti-infective adjunct to traditional antibiotic therapy.
70 Tocilizumab for Antibody-Mediated Rejection in the Setting of Cardiac Allograft Vasculopathy S. January,1 A. Pottebaum,1 D. Raymer,1 and K. Lavine.2 1Barnes-Jewish Hospital, St Louis, MO; and the 2Washington University School of Medicine, St Louis, MO.
Abstracts Introduction: IL-6 is a pro-inflammatory cytokine that potentiates the effect of plasma cells, immunoglobulins, T-cells, and macrophages. IL-6 levels are associated with atherosclerotic plaque progression and graft fibrosis; IL-6 blockade may have a role in therapy for cardiac allograft vasculopathy (CAV). Preclinical data has also implicated IL-6 signaling in graft rejection. Tocilizumab, an IL-6 receptor antagonist, has successfully decreased donor-specific antibodies (DSAs) in renal transplant patients with antibody-mediated rejection (AMR). Herein, we report on the use of tocilizumab in a heart transplant recipient with treatment-refractory AMR and established CAV. Case Report: A 65 year old male who underwent heart transplantation 13 years ago presented with dyspnea. His history was significant for AMR 5 years post-transplant and CAV 10 years post-transplant. On admission, studies revealed reduced LV ejection fraction (LVEF, 70% to 50%) and cardiac index (CI, 1.27 L/min/m2), severe 3-vessel CAV, and elevated pulmonary capillary wedge pressure (PCWP, 28 mmHg). He had new DSAs against HLA-A, -B, -DQ, and -DR antigens (MFI 5,792-24,748); biopsy grade was 1R/1A. He was treated with steroids, plasmapheresis, IVIg, and rituximab; maintenance immunosuppression was revised to tacrolimus, everolimus, mycophenolate, and prednisone. He was readmitted twice within the next month with acute decompensation requiring inotropes. He had a further decline in LVEF to 45%, CAV progression, and largely unchanged DSAs. He was again treated with steroids, plasmapheresis, and IVIg. Given progressive decline despite traditional AMR and CAV therapy, we initiated tocilizumab 800 mg monthly. He has received tocilizumab for one year without significant complications or hospitalizations; he reports NYHA class II symptoms. HLA screen showed resolution of HLAA, -B, and -DR DSAs and MFI reduction of HLA-DQ DSA (24,748 to 14,994). Right heart catheterization was significantly improved (CI 2.06 L/ min/m2 and PCWP 18 mmHg); LVEF remains unchanged and coronary angiography shows CAV progression. Summary: To our knowledge, this represents the first report of using tocilizumab for refractory cardiac AMR and CAV. Additional studies are warranted to evaluate the safety and efficacy of tocilizumab in heart transplant recipients and to elucidate the mechanism of DSA clearance by tocilizumab.
71 Expanding Benefits from Cardiac Resynchronization Therapy to Exercise-Induced Left Bundle Branch Block in the Setting of Advanced Heart Failure: A Case Report F.L. Scolari, W.R. Menegazzo, A.D. Silveira, A.C. Mendes, M. Pimentel, N. Clausell and L. Goldraich. Hospital de Clínicas Porto Alegre, Porto Alegre, Brazil. Introduction: Exercise-induced left bundle branch block (LBBB) is rarely observed in exercise testing, and usually implies a worse prognosis. Cardiac resynchronization therapy (CRT) is well validated in patients with heart failure with reduced ejection fraction (HFrEF) and LBBB. Although the indications of CRT do not include exercise-induced LBBB, the functional impairment secondary to dynamic electromechanical dyssynchrony could potentially be improved with CRT. Case Report: A 57-year-old woman with long-standing idiopathic dilated cardiomyopathy (ejection fraction of 23%) presented with clinical deterioration to NYHA functional class 4 and recurrent hospitalizations despite optimal medical treatment. During evaluation for cardiac transplant, newonset of intermittent LBBB was observed on the cardiopulmonary exercise test (her resting QRS duration was 100ms). A stress echocardiography showed exertion-induced intraventricular and interventricular dyssynchrony. Cardiac resynchronization therapy was then indicated, and 97% resynchronization rate was obtained. There was clinical improvement to NYHA class 2 and no hospitalizations since the CRT initiation. Functional reassessment at 6 and 12 months post-implant demonstrated significant improvement in prognostic exercise parameters (Figure). She currently remains off the transplant list. Summary: In HFrEF patients with no LBBB at rest, exercise test and stress echocardiography may uncover dynamic electromechanical dyssynchrony that may benefit from CRT. This is the first report of CRT for treatment of an advanced heart failure patient with worsening symptoms attributed to exercise-induced LBBB.
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72 31 Day Xeno Lung Recipient Survival - Progress towards the Clinic L. Burdorf,1 C. Laird,2 S. Sendil,2 N. O'Neill,2 T. Zhang,2 D. Parsell,2 I. Tatarov,3 Z. Abady,1 B.M. Cerel,1 S. Pratts,1 C.J. Phelps,4 D.L. Ayares,4 A.M. Azimzadeh,1 and R.N. Pierson.III.1 1Surgery, Center for Transplanation Sciences, MGH, Charlestown, MA; 2Surgery, University of Maryland, Baltimore, MD; 3Surgery, University of Maryland, Baltimore, MA; and the 4Revivicor, Blacksburg, VA. Purpose: Improved gene editing techniques have accelerated generation of genetically engineered (GE) pigs with multiple knock-outs (KO) and expression of human “transgenes” that address xenograft rejection pathways. The association between various transgene combinations and prevention of lung xenograft injury was assessed in a rigorous life-supporting pig-to-baboon lung xenograft model. Methods: GalTKO.hCD46 pigs with up to 5 additional modifications, including hCD55, hTBM, hEPCR, hTFPI, hCD47, hCD39, HO-1, HLA-E, A20, b4GalKO, Neu5GcKO, and humanized vWF (hvWF) were used in our last 48 left single lung transplants into baboons. A rationally designed “platform drug regimen” consisted of steroids, sC1Inh, thromboxane synthase inhibitor, histamine receptor blockers, and anti-GPIb Fab, and DDAVP donor pretreatment. Immunosuppression consisted of aCD20, ATG, MMF, aCD40, aIL6R, aIL8, and/or aTNF. Results: While 3- or 4-GE lungs generally were not life-supporting and recipients survived for <12-24 hrs, 6-GE organs usually were fully lifesupporting, and some combinations, particularly including hvWF, hEPCR, and hCD47, resulted in 4-7d survival, and occasionally 8d (hCD55. hEPCR.hTBM.hCD39) or 9d (hEPCR.hTBM.hCD47.HO-1) (Fig.1). One 7-GE lung (hEPCR.hTBM.hCD47.HO-1.b4GalKO) recipient survived for 31d, the longest reported to date. Lung xenograft failure after 3d was usually associated with rebounding anti-pig antibody and loss of lung vascular barrier function. Conclusion: The combination of multi-GE lungs with mechanism-directed drugs significantly prolongs life-supporting lung xenograft recipient survival. In addition to anti-non-Gal antibody, recipient NK cells (HLA-E), pvWF-GPIb platelet binding, and donor macrophages (CD47, thromboxane) each drive residual inflammation. Controlling these injury pathways with further mechanism-based GE and/or drugs coupled with improved IS appear likely to advance lung xenotransplantation towards clinical application.
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
baseline of 8.9 g/dL to 6.9 g/dL. He underwent push enteroscopy during this hospital stay which demonstrated bleeding jejunal angioplastic lesions. The PAP readings during the episodes of GI bleeding were reviewed. There was a significant reduction in PAP at the date of symptom onset from one day prior; from 57/26 mmHg (mPAP 38 mmHg) on 6/3 to 48/24 mmHg (mPAP 34 mmHg) on 6/4 corresponding with 2 g/dL drop in Hb level (See figure). This phenomenon was seen in a prior episode of GI bleeding 2 months prior. The PAP numbers dropped considerably to 39/18 mmHg (mPAP 27 mmHg) at the onset of symptoms compared with 49/22 mmHg (mPAP 33 mmHg) 1 day prior associated with 2.9 g/dL decline in Hb level. During the time PAP changes were observed, diuretic therapy was not modified. Summary: In patients implanted with CardioMEMS device, a sudden drop in PAP can herald a GI bleeding episode. Monitoring PAP trends can be helpful in LVAD patients who are at higher risk for GI bleeding.
69 Successful Bacteriophage Therapy for Treatment of MultidrugResistant Pseudomonas aeruginosa Infection in a Cystic Fibrosis Patient N. Law,1 C. Logan,1 C. Furr,2 S. Lehman,2 S. Morales,2 F. Rosas,2 A. Gaidamaka,2 I. Bilinsky,2 P. Grint,2 R. Schooley,1 and S. Aslam.1 1University of California, San Diego, San Diego, CA; and the 2 AmpliPhi Biosciences Inc, San Diego, CA.
68 Inverted Lung Transplantation: Interposition of Pericardial Conduit for Pulmonary Venous Anastomosis H. Yamamoto,1 K. Miyoshi,2 T. Kurosaki,1 S. Otani,1 M. Okazaki,1 S. Sugimoto,1 M. Yamane,1 S. Toyooka,1 and T. Oto.1 1General Thoracic Surgery, Organ Transplant Center, Okayama University Hospital, Okayama, Japan; and the 2General Thoracic Surgery, Okayama Medical Center, Okayama, Japan. Introduction: Lung transplantation (LTx) is still limited by a shortage of suitable donor lungs. Evolving flexible surgical procedures help increase the chances of LTx by unfolding recipient-to-donor matching options based on the pre-existing organ allocation concept. In particular, right single LTx using an inverted left donor lung may be considered under the following conditions: 1) Despite a right-side-predominant lung dysfunction in a recipient candidate, the option is limited to the use of a left single donor lung due to evidence of lung injury in the right donor lung or necessity to share the organ with another candidate prioritized on the waitlist; 2) Left side LTx in the recipient is impossible due to a past history in the recipient of thoracic surgery. One of the key challenges in performing inverted LTx is to adjust the positional relationship between the recipient’s and graft’s hilar structures. Herein, we report a case of successful left-to-right inverted LTx using interposition of a pericardial conduit for pulmonary venous anastomosis. Case Report: A left lung graft was offered to a 59-year-old male who had predominant damage of the right lung by idiopathic pulmonary fibrosis (Fig.1A). We decided to transplant the left donor lung into the right thorax of the recipient, considering his serious disease condition. Due to the anterior-posterior position gap, adjustment of the cuff length of the pulmonary artery and vein was required. Pulmonary artery anastomosis could be performed by leaving both the donor and recipient cuff long, but an extension of the pulmonary vein by interposition of a pericardial conduit was required for anastomosis (Fig.1B). The patient developed no anastomotic complications after the LTx. Summary: left-to-right inverted LTx is technically feasible by using an autologous pericardial conduit in selected cases. The technique has the potential benefit of encouraging exploration and expansion of unprecedented donor-recipient matching patterns in LTx.
Introduction: Bacteriophages are host-specific lytic viruses that are of increasing interest as adjunctive therapy for treatment of multi-drug resistant (MDR) pathogens. Case Report: We describe the use of bacteriophage therapy (BT) in a 26year-old cystic fibrosis (CF) patient awaiting lung transplantation who was admitted for respiratory failure requiring mechanical ventilation for 12 days. The hospital course was complicated by MDR Pseudomonas aeruginosa (PA) pneumonia, persistent respiratory failure, and colistin-induced renal failure (listed for concomitant kidney transplant). Due to worsening clinical status, BT was explored as an adjunct to antibiotics. The patient was approved under emergency IND#17710 by the FDA to receive AB-PA01 (combination of 4 lytic phages) active against the clinical PA isolates. This was given every 6 hours intravenously (IV) for 8 weeks. As noted in Figure 1, the patient was bed-bound due to severe dyspnea and required 30 L/min O2 via high flow nasal cannula (NC) at BT initiation. MDR PA pneumonia resolved by Day 7. Her respiratory status continued to improve and by end of therapy (EOT) she was on 4 L/min O2 via NC and was able to work with physical therapy. No adverse events related to BT occurred. There was no recurrent pneumonia or CF exacerbation within 90-days following the end of treatment. Renal failure resolved once off colistin and the patient was removed from the kidney transplant waitlist. Summary: We describe the successful use of BT in a CF patient awaiting lung transplant. Given the concern for MDR PA in CF patients, BT may offer a viable anti-infective adjunct to traditional antibiotic therapy.
70 Tocilizumab for Antibody-Mediated Rejection in the Setting of Cardiac Allograft Vasculopathy S. January,1 A. Pottebaum,1 D. Raymer,1 and K. Lavine.2 1Barnes-Jewish Hospital, St Louis, MO; and the 2Washington University School of Medicine, St Louis, MO.
Abstracts Introduction: IL-6 is a pro-inflammatory cytokine that potentiates the effect of plasma cells, immunoglobulins, T-cells, and macrophages. IL-6 levels are associated with atherosclerotic plaque progression and graft fibrosis; IL-6 blockade may have a role in therapy for cardiac allograft vasculopathy (CAV). Preclinical data has also implicated IL-6 signaling in graft rejection. Tocilizumab, an IL-6 receptor antagonist, has successfully decreased donor-specific antibodies (DSAs) in renal transplant patients with antibody-mediated rejection (AMR). Herein, we report on the use of tocilizumab in a heart transplant recipient with treatment-refractory AMR and established CAV. Case Report: A 65 year old male who underwent heart transplantation 13 years ago presented with dyspnea. His history was significant for AMR 5 years post-transplant and CAV 10 years post-transplant. On admission, studies revealed reduced LV ejection fraction (LVEF, 70% to 50%) and cardiac index (CI, 1.27 L/min/m2), severe 3-vessel CAV, and elevated pulmonary capillary wedge pressure (PCWP, 28 mmHg). He had new DSAs against HLA-A, -B, -DQ, and -DR antigens (MFI 5,792-24,748); biopsy grade was 1R/1A. He was treated with steroids, plasmapheresis, IVIg, and rituximab; maintenance immunosuppression was revised to tacrolimus, everolimus, mycophenolate, and prednisone. He was readmitted twice within the next month with acute decompensation requiring inotropes. He had a further decline in LVEF to 45%, CAV progression, and largely unchanged DSAs. He was again treated with steroids, plasmapheresis, and IVIg. Given progressive decline despite traditional AMR and CAV therapy, we initiated tocilizumab 800 mg monthly. He has received tocilizumab for one year without significant complications or hospitalizations; he reports NYHA class II symptoms. HLA screen showed resolution of HLAA, -B, and -DR DSAs and MFI reduction of HLA-DQ DSA (24,748 to 14,994). Right heart catheterization was significantly improved (CI 2.06 L/ min/m2 and PCWP 18 mmHg); LVEF remains unchanged and coronary angiography shows CAV progression. Summary: To our knowledge, this represents the first report of using tocilizumab for refractory cardiac AMR and CAV. Additional studies are warranted to evaluate the safety and efficacy of tocilizumab in heart transplant recipients and to elucidate the mechanism of DSA clearance by tocilizumab.
71 Expanding Benefits from Cardiac Resynchronization Therapy to Exercise-Induced Left Bundle Branch Block in the Setting of Advanced Heart Failure: A Case Report F.L. Scolari, W.R. Menegazzo, A.D. Silveira, A.C. Mendes, M. Pimentel, N. Clausell and L. Goldraich. Hospital de Clínicas Porto Alegre, Porto Alegre, Brazil. Introduction: Exercise-induced left bundle branch block (LBBB) is rarely observed in exercise testing, and usually implies a worse prognosis. Cardiac resynchronization therapy (CRT) is well validated in patients with heart failure with reduced ejection fraction (HFrEF) and LBBB. Although the indications of CRT do not include exercise-induced LBBB, the functional impairment secondary to dynamic electromechanical dyssynchrony could potentially be improved with CRT. Case Report: A 57-year-old woman with long-standing idiopathic dilated cardiomyopathy (ejection fraction of 23%) presented with clinical deterioration to NYHA functional class 4 and recurrent hospitalizations despite optimal medical treatment. During evaluation for cardiac transplant, newonset of intermittent LBBB was observed on the cardiopulmonary exercise test (her resting QRS duration was 100ms). A stress echocardiography showed exertion-induced intraventricular and interventricular dyssynchrony. Cardiac resynchronization therapy was then indicated, and 97% resynchronization rate was obtained. There was clinical improvement to NYHA class 2 and no hospitalizations since the CRT initiation. Functional reassessment at 6 and 12 months post-implant demonstrated significant improvement in prognostic exercise parameters (Figure). She currently remains off the transplant list. Summary: In HFrEF patients with no LBBB at rest, exercise test and stress echocardiography may uncover dynamic electromechanical dyssynchrony that may benefit from CRT. This is the first report of CRT for treatment of an advanced heart failure patient with worsening symptoms attributed to exercise-induced LBBB.
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72 31 Day Xeno Lung Recipient Survival - Progress towards the Clinic L. Burdorf,1 C. Laird,2 S. Sendil,2 N. O'Neill,2 T. Zhang,2 D. Parsell,2 I. Tatarov,3 Z. Abady,1 B.M. Cerel,1 S. Pratts,1 C.J. Phelps,4 D.L. Ayares,4 A.M. Azimzadeh,1 and R.N. Pierson.III.1 1Surgery, Center for Transplanation Sciences, MGH, Charlestown, MA; 2Surgery, University of Maryland, Baltimore, MD; 3Surgery, University of Maryland, Baltimore, MA; and the 4Revivicor, Blacksburg, VA. Purpose: Improved gene editing techniques have accelerated generation of genetically engineered (GE) pigs with multiple knock-outs (KO) and expression of human “transgenes” that address xenograft rejection pathways. The association between various transgene combinations and prevention of lung xenograft injury was assessed in a rigorous life-supporting pig-to-baboon lung xenograft model. Methods: GalTKO.hCD46 pigs with up to 5 additional modifications, including hCD55, hTBM, hEPCR, hTFPI, hCD47, hCD39, HO-1, HLA-E, A20, b4GalKO, Neu5GcKO, and humanized vWF (hvWF) were used in our last 48 left single lung transplants into baboons. A rationally designed “platform drug regimen” consisted of steroids, sC1Inh, thromboxane synthase inhibitor, histamine receptor blockers, and anti-GPIb Fab, and DDAVP donor pretreatment. Immunosuppression consisted of aCD20, ATG, MMF, aCD40, aIL6R, aIL8, and/or aTNF. Results: While 3- or 4-GE lungs generally were not life-supporting and recipients survived for <12-24 hrs, 6-GE organs usually were fully lifesupporting, and some combinations, particularly including hvWF, hEPCR, and hCD47, resulted in 4-7d survival, and occasionally 8d (hCD55. hEPCR.hTBM.hCD39) or 9d (hEPCR.hTBM.hCD47.HO-1) (Fig.1). One 7-GE lung (hEPCR.hTBM.hCD47.HO-1.b4GalKO) recipient survived for 31d, the longest reported to date. Lung xenograft failure after 3d was usually associated with rebounding anti-pig antibody and loss of lung vascular barrier function. Conclusion: The combination of multi-GE lungs with mechanism-directed drugs significantly prolongs life-supporting lung xenograft recipient survival. In addition to anti-non-Gal antibody, recipient NK cells (HLA-E), pvWF-GPIb platelet binding, and donor macrophages (CD47, thromboxane) each drive residual inflammation. Controlling these injury pathways with further mechanism-based GE and/or drugs coupled with improved IS appear likely to advance lung xenotransplantation towards clinical application.