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• An injectable decellularized extracellular matrix hydrogel is developed to deliver exosomes encapsulating curcumin locally to the infarcted area of the heart. • The solubility and bioavailability of curcumin are enhanced by exosomal encapsulation, and the hydrogel improves the retention of exosomes. • Intramyocardial injection of this hydrogel promotes angiogenesis, decreases collagen deposition, and prevents cardiac fibrosis to facilitate cardiac repair after myocardial infarction. Excessive cardiac fibrosis impairs cardiac repair after myocardial infarction (MI). In this work, an injectable composite hydrogel integrating natural biomaterials, exosomes, and bioactive molecules is developed to prevent or alleviate cardiac fibrosis. Curcumin, a natural molecule with antifibrotic activity, is encapsulated in the exosomes that are isolated from bone marrow-derived mesenchymal stem cells to enhance its water solubility and bioavailability. These composite exosomes are efficiently internalised by fibroblasts and effectively inhibit their transition to myofibroblasts in vitro. Decellularized porcine cardiac extracellular matrix (dECM) hydrogel is used as the carrier for delivering these composite exosomes to the infarcted myocardium, not only improving the retention of exosomes but also providing mechanical support and structural protection. Injection of this hydrogel into the infarcted heart of a mouse MI model leads to a decrease in collagen deposition, alleviation of fibrosis, a reduction in infarct size, and an improvement in cardiac function. The reported composite hydrogel comprising natural materials and biomolecules exhibits good biocompatibility and bioactivity. Altogether, this study demonstrates that the dECM hydrogel is a suitable platform for the local delivery of antifibrotic biomolecule-encapsulating exosomes to prevent myocardial fibrosis after MI and have great potential for the treatment of MI in clinical settings. [Display omitted] [ABSTRACT FROM AUTHOR]

• An injectable alginate/fibrin hydrogel is developed to deliver cardiomyocytes and VEGF locally to the infarcted area of the heart. • This hydrogel supports the retention and integration of the transplanted cardiomyocytes into the host myocardium. • The delivered VEGF is favorable for blood recovery to improve the survival of cardiomyocytes. • Intramyocardial injection of this hydrogel promotes angiogenesis, inhibits fibrosis, and improves cardiac function after myocardial infarction. Myocardial infarction (MI) is one of the typical cardiovascular diseases, which persist as the leading cause of death globally. Due to the poor regenerative capability of endogenous cardiomyocytes (CMs), the transplantation of exogenous CMs becomes a promising option for MI treatment. However, the low retention and survival of transplanted cells still limit the clinical translation of cell therapy. Herein, an alginate/fibrin-based injectable hydrogel was prepared for the delivery of neonatal CMs and an angiogenesis agent vascular endothelial growth factor (VEGF) locally to the infarcted area of the heart. This hydrogel combined the specific advantages of alginate and fibrin with proper mechanical properties and cell affinity, showing good biocompatibility to support the retention and integration of the transplanted CMs to the host myocardium. Moreover, the delivered VEGF was favorable for the blood recovery to mitigate the ischemic microenvironment of the infarcted area and thus improved the survival of the transplanted CMs. Intramyocardial injection of this hydrogel to the infarcted area of the heart promoted angiogenesis, inhibited fibrosis, and improved cardiac function, exhibiting great potential for MI treatment. [ABSTRACT FROM AUTHOR]

Transplantation of exogenous cardiomyocytes (CMs) is a hopeful method to treat myocardial infarction (MI). However, its clinical application still remains challenging due to low retention and survival rates of the transplanted cells. Herein, a stromal cell-derived factor 1 (SDF-1)-loaded injectable hydrogel based on a decellularized porcine extracellular matrix (dECM) is developed to encapsulate and deliver CMs locally to the infarct area of the heart. The soluble porcine cardiac dECM is composed of similar components such as the human cardiac ECM, which could be self-assembled into a nanofibrous hydrogel at physiological temperature to improve the retention of transplanted CMs. Furthermore, the chemokine SDF-1 could recruit endogenous cells to promote angiogenesis, mitigating the ischemic microenvironment and improving the survival of CMs. The results in vitroshow that this composite hydrogel exhibits good biocompatibility, anti-apoptosis property, and chemotactic effects for mesenchymal stromal cells and endothelial cells through SDF-1-CXCR4 axis. Moreover, intramyocardial injection of this composite hydrogel to the infarcted area leads to the promotion of angiogenesis and inhibition of fibrosis, reducing the infarction size and improving the cardiac function. The combination of natural biomaterials, exogenous cells, and bioactive factors shows potential for MI treatment in the clinical application.

• Biomaterials used for cardiac patches are classified according to their sources. • The required properties for the biomaterials to make cardiac patches are introduced. • The specific advantages and shortcomings of different types of cardiac patches are discussed. • The development tendency of biomaterials based cardiac patches is prospected. Myocardial infarction (MI) is one of the common cardiovascular diseases that occurs with a blockage in one or more of the coronary arteries to lead to the damage of the myocardium, resulting in a life-threatening condition. To repair the damaged myocardium in MI, researchers are looking forwards to new ways to postpone the progression of myocardial injury. Cardiac patches, the scaffolds layered on the heart surface, can provide mechanical support for the infarction site and improve cardiac function by delivering various bioactive factors or cells, showing considerable curative effect in the treatment of MI. Biomaterials with certain biocompatibility and mechanical properties have received widespread attention for the application in cardiac patches. In this review, we focus on the recent progress on these biomaterials-based cardiac patches, which could be categorized into two types according to the sources of materials including (ⅰ) natural materials and (ⅱ) synthetic materials. The major advantages and current challenges of each type are discussed and a brief perspective on the future research directions is presented. [Display omitted] [ABSTRACT FROM AUTHOR]

Byline: Zhenya Shen, Muhammad Mohiuddin, Hitoshi Yokoyama, G.Russell Reiss, Verdi J. DiSesa Abstract: Indefinite donor-specific tolerance to a cardiac allograft can be induced through pretransplantation intrathymic injection of donor spleen cells and a single intraperitoneal injection of antilymphocyte serum. This study was designed to determine whether this phenomenon was reproducible with grafts differing in either class I major histocompatibility complex only or class II MHC only. Donors of cells and hearts in all experiments were RP rats. Class I MHC disparate grafts were performed by placing an RP heart into a Lewis recipient, and class II disparate grafts were performed with RP donors and Wistar Furth recipients. Lewis (n = 10) and Wistar Furth (n = 10) recipients underwent intraperitoneal injection of 1 ml antilympocyte serum and intrathymic injection of 5 x 10.sup.7 RP spleen cells. Three weeks later, heterotopic cardiac transplantation was done with a heart from an RP rat. Control rats had no pretreatment or received antilympocyte serum alone. Without pretreatment, RP hearts survived 7 to 9 days (mean 8 days) in Lewis recipients (n = 5) and 9 to 14 days (mean 12 days) in Wistar Furth recipients (n = 5). Antilymphocyte serum alone produced slight prolongation of graft survival. Lewis rats pretreated with class I disparate RP splenocytes and antilympocyte serum had graft survivals of 8 to 27 days (mean 14 days), not significantly different from the results with antilympocyte serum alone. Class II disparate RP grafts placed in pretreated Wistar Furth rats had significant prolongation of graft survival, with four of five grafts surviving longer than 60 days (p < 0.01 vs antilympocyte serum alone). These results suggest that a disparity at the class II locus of the major histocompatibility complex is critical for the induction of cardiac allograft tolerance after intrathymic inoculation of allogeneic cells. (J T HORAC CARDIOVASC SURG 1996;112:1315-8) Article History: Received 25 March 1996; Revised 8 May 1996; Revised 17 May 1996; Accepted 21 May 1996 Article Note: (footnote) [star] From the Department of Cardiothoracic Surgery, The Medical College of Pennsylvania and Hahnemann University School of Medicine, Philadelphia, Pa., [star][star] Read at the Seventy-sixth Annual Meeting of The American Association for Thoracic Surgery, San Diego, Calif., April 28-May 1, 1996., a Address for reprints: Verdi J. DiSesa, M.D., Cardiothoracic Surgery, Medical College of Pennsylvania Hospital, 3300 Henry Avenue, Philadelphia, PA 19129., aa 0022-5223/96 $5.00 + 0, acents 12/6/75200

Byline: Muhammad Mohiuddin, Vincent Ruggiero, Zhenya Shen, Verdi J. DiSesa Abstract: To study the molecular immunologic features of allograft rejection and tolerance induction by intrathymic pretreatment we developed a murine model of cardiac transplantation. In this model the transplant recipient was the C57BL/6 mouse with its major histocompatibility phenotype H-2.sup.b. Donors of cells for intrathymic pretreatment and of hearts for grafting were mice of the bm1 mutation. The bm1 mutation involves substitution of three amino acids in one of the alpha helixes of the class I H-2K.sup.b molecule. Because of the discrete molecular configuration of the transplant antigen we hypothesized that there would be limited heterogeneity of receptor expression on C57BL/6 T cells responding to bm1 cardiac grafts and that intrathymic pretreatment would alter the T-cell repertoire of graft recipients by causing elimination of T cells responsible for graft rejection. Mice were given 0.3 ml of antilymphocyte serum intraperitoneally and had intrathymic injection of 25 x 10.sup.6 bm1 splenocytes 12 to 21 days before transplantation with a bm1 cardiac graft. Flow cytometric analysis of lymph node and spleen cells was used to study the V beta T-cell repertoire of graft recipients. Cells were stained with monoclonal antibodies to CD3 and 13 V beta regions (n = 5, each group) of T cells in naive, sensitized, and tolerant animals. Untreated C57BL/6 mice (n = 9) rejected bm1 cardiac grafts a mean of 20.4 days after transplantation. Twelve mice pretreated with antilymphocyte serum and intrathymic bm1 cells had permanent graft survival (>100 days, p < 0.0001). Animals treated with antilymphocyte serum alone (n = 5) or pretreated animals undergoing third-party BALB/c grafts (n = 4) rejected grafts in the normal time frame. There was significant alteration of percentage receptor expression of V beta 5.1, 7, 12, 13, and 17a in sensitized and tolerant mice. Of interest, V beta 7 expression was increased in the sensitized mice (3.8% to 8.3%, p = 0.005) and was virtually eliminated in tolerant mice (p = 0.005). In conclusion, these data suggest that V beta 7 is a critical receptor in the C57BL/6 response to subcutaneous bm1 cardiac grafts. Pretreatment of graft recipients with one dose of antilymphocyte serum and intrathymic bm1 cells appears to produce permanent tolerance to bm1 grafts with elimination of T cells expressing receptor chain V beta 7. (J Thorac Cardiovasc Surg 1996;112:310-3) Article History: Received 12 May 1995; Revised 17 August 1995; Revised 27 November 1995; Accepted 5 December 1995 Article Note: (footnote) [star] From the Department of Surgery, Medical College of Pennsylvania, Philadelphia, Pa., [star][star] Address for reprints: Verdi J. DiSesa, MD, Cardiothoracic Surgery, The Medical College of Pennsylvania, 3300 Henry Ave., Philadelphia, PA 19129., a 0022-5223/96 $5.00 + 0, aa 12/1/71012

Myocardial infarction (MI) is one of cardiovascular diseases that pose a serious threat to human health. The pathophysiology of MI is complex and contains several sequential phases including blockage of a coronary artery, necrosis of myocardial cells, inflammation, and myocardial fibrosis. Aiming at the treatment of different stages of MI, in this work, an injectable alginate based composite hydrogel is developed to load vascular endothelial active factor (VEGF) and silk fibroin (SF) microspheres containing bone morphogenetic protein 9 (BMP9) for releasing VEGF and BMP9 to realize their respective functions. The results of in vitroexperiments indicate a rapid initial release of VEGF during the first few days and a relatively slow and sustained release of BMP9 for days, facilitating the formation of blood vessels in the early stage and inhibiting myocardial fibrosis in the long-term stage, respectively. Intramyocardial injection of such composite hydrogel into the infarct border zone of mice MI model via multiple points promotes angiogenesis and reduces the infarction size. Taken together, these results indicate that the dual-release of VEGF and BMP9 from the composite hydrogel results in a collaborative effect on the treatment of MI and improvement of heart function, showing a promising potential for cardiac clinical application.

Byline: Zhenya Shen, Muhammad Mohiuddin, Charles Goldstein, Hitoshi Yokoyama, Verdi J. DiSesa Abstract: Permanent acceptance of an experimental cardiac allograft can be achieved in the rat by pretreating the recipient with antilymphocyte serum and intrathymic donor lymphocytes. We investigated the durability and specificity of the tolerance produced by this pretreatment in a rat model of heterotopic heart transplantation with Lewis-Brown Norway donors and Lewis recipients. Pretreated Lewis rats received 1 ml antilymphocyte serum intraperitoneally and 5 x 10.sup.7 Lewis-Brown Norway splenocytes intrathymically, followed 21 days later by Lewis-Brown Norway cardiac transplantation. The first Lewis-Brown Norway cardiac allograft survived long term (mean 140 days) in pretreated recipients who were given no subsequent immunosuppression. After 60 days with a beating Lewis-Brown Norway allograft, tolerant Lewis recipients underwent a second cardiac allograft with either a Lewis-Brown Norway heart or a third-party Wistar-Furth heart. The second Lewis-Brown Norway cardiac allograft was not rejected (mean survival 76 days), but that from the third-party Wistar-Furth donor was rejected in a normal fashion (mean survival 10.4 days). The presence of second grafts did not affect survival of first grafts. Tolerant Lewis recipients of two Lewis-Brown Norway heart grafts underwent subsequent transplantation with Lewis-Brown Norway skin. Skin allograft survival in this group (mean 8.4 days) was not different from that in Lewis recipients without pretreatment. Rejection of skin grafts had no effect on the heart grafts. These data suggest that tolerance to cardiac allografts produced by intrathymic pretreatment is durable and extends to a second heart graft from a genetically identical donor. Tolerant rats reject third-party hearts and primary donor skin grafts normally, and tolerance to previously placed heart grafts is not abrogated by this rejection. Non-major histocompatibility complex skin antigens not present on cardiac cells may account for the tissue specificity of the tolerance produced by intrathymic treatment in this model. (J THORAC CARDIOVASC SURG 1996;111:429-31) Author Affiliation: Philadelphia, Pa. Article History: Received 27 March 1995; Accepted 23 May 1995 Article Note: (footnote) [star] From the Department of Surgery, Medical College of Pennsylvania and Hahnemann University, Philadelphia., [star][star] Address for reprints: Verdi J. DiSesa, MD, Cardiothoracic Surgery, Medical College of Pennsylvania, 3300 Henry Ave., Philadelphia, PA 19129., a 0022-5223/96 $5.00 + 0, aa 12/1/66458

Myocardial infarction (MI) is associated with inflammatory reaction, which is a pivotal component in MI pathogenesis. Moreover, excessive inflammation post-MI can lead to cardiac dysfunction and adverse remodeling, emphasizing the critical need for an effective inflammation-regulating treatment for cardiac repair. Macrophage polarization is crucial in the inflammation process, indicating its potential as an adjunct therapy for MI. In this study, we developed an injectable alginate hydrogel loaded with annexin A1 (AnxA1, an endogenous anti-inflammatory and pro-resolving mediator) for MI treatment. In vitro results showed that the composite hydrogel had good biocompatibility and consistently released AnxA1 for several days. Additionally, this hydrogel led to a reduced number of pro-inflammatory macrophages and an increased proportion of pro-healing macrophages via the adenosine monophosphate (AMP)-activated protein kinase (AMPK)-mammalian target of the rapamycin (mTOR) axis. Furthermore, the intramyocardial injection of this composite hydrogel into a mouse MI model effectively modulated macrophage transition to pro-healing phenotypes. This transition mitigated early inflammatory responses and cardiac fibrosis, promoted angiogenesis, and improved cardiac function. Therefore, our study findings suggest that combining biomaterials and endogenous proteins for MI treatment is a promising approach for limiting adverse cardiac remodeling, preventing cardiac damage, and preserving the function of infarcted hearts.

Nanoparticle-mediated drug delivery has emerged as a highly promising and effective therapeutic approach for addressing myocardial infarction. However, clinical translation tends to be a failure due to low cardiac retention as well as liver and spleen entrapment in previous therapies. Herein, we report a two-step exosome delivery system, which precludes internalization by the mononuclear phagocyte system before the delivery of therapeutic cardiac targeting exosomes (ExoCTP). Importantly, curcumin released by ExoCTPdiminishes reactive oxygen species over-accumulation in ischemic myocardium, as well as serum levels of lactate dehydrogenase, malonyldialdehyde, superoxide dismutase and glutathione, indicating better antioxidant capacity than free curcumin. Finally, our strategy was proven to greatly potentiate the delivery and therapeutic efficacy of curcumin without systemic toxicity. Taken together, our smart exosome-mediated drug delivery strategy can serve either as therapeutics alone or in combination with other drugs for effective heart targeting and subsequent wound healing.

Myocardial infarction (MI), with a major process of cardiomyocyte death, remains a leading cause of morbidity and mortality worldwide. To date, it has been shown that lncRNAs play important roles in cardiovascular pathology. However, the detailed studies on lncRNAs regulating cardiomyocyte death in myocardial infarction are still limited. In this study, we found a progressively upregulated expression of Meg3in mouse injured heart after MI. Gain-of-function and loss-of-function approaches further revealed pro-apoptotic functions of Meg3in rodent cardiomyocytes. Moreover, Meg3was directly upregulated by p53 in hypoxic condition, and involved in apoptotic regulation via its direct binding with RNA-binding protein FUS (fused in sarcoma). Afterwards, adult MI mice that underwent intramyocardial injection with adeno-associated virus serotype 9 (AAV9) system carrying Meg3shRNA showed a significant improvement of cardiac function. Moreover, we also found that MEG3was increased in clinical heart failure samples, and had conservatively pro-apoptotic function in human cardiomyocytes that were differentiated from the human embryonic stem cells. Together, these results indicate that p53-induced Meg3–FUS complex plays an important role in cardiomyocyte apoptosis post-MI, and its specific knockdown in cardiomyocytes with AAV9 system represents a promising method to treat MI for preclinical investigation.

Bone marrow stem cell (BMSC) transplantation during coronary artery bypass graft (CABG) is an innovative treatment for ischemic heart disease (IHD). We conduct a meta-analysis to examine whether patients with IHD presenting heart failure with reduced ejection fraction (HFrEF) can be beneficent from CABG with additional BMSC transplantation. Electronic searches were performed on PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov from their inception to July 2021. The efficacy was based on left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), left ventricular end-diastolic volume (LVEDV), left ventricular end-diastolic volume index (LVEDVi), left ventricular end-systolic volume index (LVESVi), and 6-min walk test (6MWT) change after treatment. Eight randomized-controlled trials (RCTs) were included in this meta-analysis, with a total of 350 patients. Results showed BMSC transplantation significantly improved the LVEF [mean difference (MD) = 6.23%, 95% confidence interval (CI): 3.22%–9.24%, P< 0.0001], LVEDVi (MD = −20.15 ml/m2, 95% CI: −30.49 to −9.82 ml/m2, P< 0.00001), and LVESVi (MD = −17.69 ml/m2, 95% CI: −25.24 to −10.14 ml/m2, P< 0.00001). There was no statistically significant difference in the improvement of LVEDD, LVEDV, and 6MWT between the cell transplantation group and control groups. Subgroup analysis revealed that the intervention for control group could affect the efficacy of BMSC transplantation. Sensitivity analysis found the conclusion of LVEDD, LVEDV, and 6MWT changes was not stable. Therefore, among patients with IHD presenting HFrEF, BMSC transplantation during CABG is promising to be beneficial for postoperative left ventricular (LV) function improvement. However, according to the unstable results of the sensitivity analysis, it cannot be concluded whether the extra step has a positive effect on left ventricular remodeling and exercise capacity. RCTs with larger cohorts and more strict protocols are needed to validate these conclusions.

Myocardial infarction (MI) is a cardiovascular disease that poses a serious threat to human health. Uncontrolled and excessive cardiac fibrosis after MI has been recognized as a primary contributor to mortality by heart failure. Thus, prevention of fibrosis or alleviation of fibrosis progression is important for cardiac repair. To this end, a biocompatible microneedle (MN) patch based on gelatin is fabricated to load exosomes containing microRNA‐29b (miR‐29b) mimics with antifibrotic activity to prevent excessive cardiac fibrosis after MI. Exosomes are isolated from human umbilical cord mesenchymal stem cells and loaded with miR‐29b mimics via electroporation, which can be internalized effectively in cardiac fibroblasts to upregulate the expression of miR‐29b and downregulate the expression of fibrosis‐related proteins. After being implanted in the infarcted heart of a mouse MI model, the MN patch can increase the retention of loaded exosomes in the infarcted myocardium, leading to alleviation of inflammation, reduction of the infarct size, inhibition of fibrosis, and improvement of cardiac function. This design explored the MN patch as a suitable platform to deliver exosomes containing antifibrotic biomolecules locally for the prevention of cardiac fibrosis, showing the potential for MI treatment in clinical applications. A biocompatible microneedle patch is developed to deliver exosomes containing microRNA‐29b mimics with antifibrotic activity to prevent excessive cardiac fibrosis after myocardial infarction. This design takes the specific advantages of the microneedle patch, the exosome, and microRNA together into one system, showing promising potential for clinical application to treat myocardial infarction.

It is still unclear whether the timing of intracoronary stem cell therapy affects the therapeutic response in patients with myocardial infarction. The natural course of healing the infarction and the presence of putative homing signals within the damaged myocardium appear to favor cell engraftment during the transendothelial passage in the early days after reperfusion. However, the adverse inflammatory environment, with its high oxidative stress, might be deleterious if cells are administered too early after reperfusion. Here we highlight several aspects of the timing of intracoronary stem cell therapy. Our results showed that transplantation of bone marrow mesenchymal stem cells at 2–4 weeks after myocardial infarction is more favorable for reduction of the scar area, inhibition of left ventricular remodeling, and recovery of heart function. Coronary injection of autologous bone marrow mesenchymal stem cells at 2–4 weeks after acute myocardial infarction is safe and does not increase the incidence of complications.

In 2006, Dr Shinya Yamanaka succeeded to reprogram somatic cells into pluripotent stem cells (iPSC) by delivering the genes encoding Oct4, Sox2, Klf4, and c-Myc. This achievement represents a fundamental breakthrough in stem cell biology and opens up a new era in regenerative medicine. However, the molecular processes by which somatic cells are reprogrammed into iPSC remain poorly understood. In 2009, Yamanaka proposed the elite and stochastic models for reprogramming mechanisms. To date, many investigators in the field of iPSC research support the concept of stochastic model, i.e., somatic cell reprogramming is an event of epigenetic transformation. A mathematical model, f(Cd, k), has also been proposed to predict the stochastic process. Here we wish to revisit the Yamanaka model and summarize the recent advances in this research field.

The objective of this study was to screen mouse bone marrow mesenchymal stromal cells (BMSCs) according to expression of cardiac stem cell (CSC) surface antigens and to assess the effects of resulting BMSC-like subsets on cardiac function after injection in a mouse myocardial infarct model. BMSCs were sorted by magnetic beads according to the expression of differentiation antigens on the surface of mouse CSCs, and four subsets were identified on the basis of CD45 and CD31 expression: stem cell antigen-1+ (Sca-1+)/CD45−/CD31−, Sca-1+/CD45−/CD31+, Sca-1+/CD45+/CD31−, and Sca-1+/CD45+/CD31+. When co-cultured with myocardial stem cells and 5-aza-2′-deoxycytidine for 14 days, each subset showed expression of cardiac markers α-actin, connexin 43, desmin, and cardiac troponin I; however, expression was greatest in Sca-1+/CD45+/CD31+ cells. To assess the ability of these cells to improve cardiac function, each subset was injected separately into mice with myocardial infarct induced by ligation of the left anterior descending coronary artery, and in vivocardiac dual inversion recovery (DIR) imaging and Doppler echocardiography were performed 48h, 96h, and 7 days after injection. Results indicated that Sca-1+/CD45+/CD31+ cells were superior in improving cardiac function compared with the other subsets and with unsorted BMSCs. These results suggest that mouse BMSC cells are polyclonal and that the BMSC-like Sca-1+/CD45+/CD31+ subset was effective in directing cardiac differentiation and improving cardiac function in mice with myocardial infarcts.

Permanent tolerance to an experimental cardiac allograft can be achieved by pretransplantation intrathymic inoculation of donor-specific lymphoid cells. We studied the effects of intrathymic inoculation of xenogeneic cells and intravenous cobra venom factor in a rodent model of cardiac xenotransplantation. Lewis rats underwent intraabdominal heterotopic heart transplantation with Syrian hamster donors. In untreated animals, mean graft survival time was 3 days. Five rats had 1 ml of antilymphocyte serum administered intraperitoneally. One day later, 2.5 × 107hamster spleen cells were inoculated into the thymus under direct vision. Twenty-one days after antilymphocyte serum was given, heterotopic heart transplantation with a hamster donor was carried out. In all cases, rejection was accelerated and occurred between 20 minutes and 1 day after transplantation. Mean graft survival time was 5.2 hours (p < 0.0001 versus control). Six animals treated with antilymphocyte serum and intrathymic xenogeneic cells had 0.5 ml of cobra venom factor, a complement antagonist, administered intravenously 3 hours before transplantation and every other day thereafter. Mean graft survival was 3 days, which was not different from the response of naive animals. Animals treated with antilymphocyte serum only had no prolongation of graft survival (mean survival time 3 days, p = not significant). Animals treated with cobra venom factor alone (n = 5) before transplantation and on alternate days subsequently had mild graft prolongation with a mean survival time of 4 days (p = 0.0133). In contrast to experimental allograft models, intrathymic inoculation of xenogeneic cells produces hyperacute rejection in these naturally concordant species. The administration of cobra venom factor abrogates the hyperacute response, but the combination of cobra venom factor and intrathymic inoculation does not produce long-term graft survival. (J Thorac Cardiovasc Surg1993;106:632-5)

Permanent tolerance to an experimental heterotopic cardiac allograft can be achieved by pretreatment with antilymphocyte serum (ALS) and intrathymic inoculation of donor cells. Most successful experimental protocols have employed a time lag of 2 to 3 weeks between intrathymic pretreatment and transplantation, which makes this treatment strategy impractical for clinical heart transplantation. In these experiments we modified the standard protocol by giving ALS 24 hr prior to both intrathymic injection of donor cells and heterotopic transplantation. Seven Lewis rats had intraperitoneal injection of 1 ml of ALS and 24 hr later underwent intrathymic injection of 5 × 107donor Lewis-Brown Norway (LBN) splenocytes and heterotopic cardiac transplantation using an LBN donor. Mean graft survival was 24.4 days, significantly longer than the 7.8-day graft survival observed in untreated Lewis recipients (n= 5) (P< 0.02). However, graft survival was not different from that observed in Lewis rats pretreated with ALS alone (n= 5) (25.8 days,P= NS). Permanent graft survival was produced in two rats receiving only ALS and in one rat receiving both ALS and intrathymic inoculation. In these experiments it appears that prolongation of graft survival may have been due to the effect of ALS alone. These results suggest that there is a critical time period between intrathymic inoculation and transplantation that is needed for permanent tolerance to be induced consistently. This may be due to the kinetics of the effects of ALS on alloreactive T-lymphocytes or to a time-dependent requirement for antigen processing in the thymus.

To determine the pulmonary pathological changes in patients of hematological malignancies with pulmonary complications using surgical or thoracoscopic technologie.17 hematological malignant patients who underwent surgical treatment were evaluated retrospectively in our study. Pulmonary infection was presented in 14 cases following chemotherapy, and lesions can not be completely absorbed after a broad-spectrum anti-bacterial and anti-fungal treatment. Furthermore, computerized tomographic scanning showed that there remained several kinds of localized lesions. Subsequently, all the 17 patients underwent open lung or thoracoscopic biopsies (lobar, partial, or wedge resection). The pathological changes of all the surgical specimens were examined postoperatively by standard hematoxylin and eosin staining.Pathological examination confirmed: Aspergillus infection in 9 patients, sub-acute inflammation (fibrosis and hematoma formation) in 3 patients, pulmonary infarction with granulomatous tissue in the periphery in 1 patient, granulomatous inflammation with calcified tubercle in 1 patient, alveolar dilation and hemorrhage, interstitial fibrosis and focal vasculitis in 1 patient, intercostal neurilemmoma in 1 patient, and moderate-differentiated adenocarcinoma accompanied by intrapulmonary metastasis in 1 patient. And several operative complications (1 case of fungal implantation, 3 cases of pleural effusion and adhesions and 2 cases of pulmonary hematoma) were occurred. The coincidence rate of pre- and post-operative diagnosis was 9/14 (64.3%). After surgery, 8 patients were received hematopoietic stem cell transplantation (HSCT, allo-gene or autologous), in which 7 cases were succeeded. Following the effective secondary antifungal prophylaxis,4 of 5 patients of aspergillosis were succeeded in transplantation free from mycotic relapse,just one patient was dead from fungal relapse.Hematological malignancies with certain pulmonary complications, that is, persistent and/or medical-management-resistant pulmonary infection, hemoptysis, or lung diseases of diagnosis unknown, should be treated in time by surgical resection to effectively eliminate the residual disease and to achieve definitive diagnosis, so as to create a prerequisite condition for the following treatments. Moreover, the secondary antifungal prophylaxis could provide positive roles in protecting patients scheduled for chemotherapy and/or HSCT.hematological malignancies; immunocompromise; pulmonary aspergillosis; pulmonary resection; histopathology ; secondary antifungal prophylaxisNo relevant conflicts of interest to declare.