Treatment of recurrent rejection in heart transplantation: cytolytic therapy or bolus steroids?

OBJECTIVES: The treatment of recurrent rejection in heart transplant recipients has been a controversial issue for many years. The intent of this retrospective study was to perform a risk-benefit analysis between treatment strategies with bolus steroids only versus anti-thymocyte globulins (RATG; 1.5 mg/kg q 4 days). METHODS: Between 1986 and 1993, 69 of 425 patients (17 male, 52 female; mean age 44 +/- 11 years) who had more than one rejection/patient per month (rej/pt per mo) in the first 3 postoperative months were defined as recurrent rejectors. RESULTS: Repetitive methylprednisolone bolus therapy (70 mg/kg q 3 days) was given in 27 patients (group M; 1.4 +/- 0.2 rej/pt per mo) and RATG therapy for one of the rejection episodes of the 42 remaining patients (group A; 1.5 +/- 0.2 rej/pt per mo). The quality of triple drug immunosuppression in the two study groups was comparable. The rejection-free interval (RFI) following RATG treatment in group A was 21.6 +/- 10 days and 22 +/- 11 in group M. In group M, 3 of 27 patients (11%) had a rejection treatment-related infection (2 bacterial; 1 viral) versus 6 of the 42 patients of group A (14.2%; bacterial 1, viral 5). During postoperative months 3-24, 0.15 +/- 0.12 rej/pat per mo were observed in group M and 0.21 +/- 0.13 rej/pat per mo in group A (n.s.). In this 21-month period cytolytic therapy for rejection was initiated in 8 of the remaining 21 patients of group M (38%) and 15 of the remaining 37 patients of group A (40.5%). The absolute survival and the individual causes of death were not affected by the type of initial treatment of recurrent rejection. The actuarial freedom of graft atherosclerosis is comparable in the two groups with 78% in group A versus 79% in group M free of graft atherosclerosis at 3 years postoperatively. CONCLUSIONS: A comparison of cytolytic therapy versus repeated applications of bolus steroids for treatment of recurrent rejection reveals no significant difference in the long-term patient outcome with respect to the incidence of future rejection episodes and survival.

Tricuspid valve regurgitation attributable to endomyocardial biopsies and rejection in heart transplantation

In the present report the prevalence, severity, and risk factors of tricuspid valve regurgitation (TR) in 251 heart transplant recipients have been analyzed retrospectively. Tricuspid valve function was studied by color-flow Doppler echocardiogram and annual heart catheterization. The presence or severity of TR was graded on a scale from 0 (no TR) to 4 (severe). Additional postoperative data included rate of rejection, number of endomyocardial biopsies, incidence of transplant vasculopathy, and preoperative and postoperative hemodynamics. The incidence of grade 3 TR increases from 5% at 1 year to 50% at 4 years after transplantation. Multivariate analysis showed rate of rejection and donor heart weight to be significant risk factors. The ischemic intervals as well as the preoperative and postoperative pulmonary hemodynamics did not affect the severity or prevalence of TR. These results indicate that various factors appear to have an impact on the development of TR and that the prevalence might be lowered by a reduction of the number of biopsies performed and when possible, oversizing of donor hearts.

The impact of early postoperative cyclosporine serum levels on the incidence of cardiac allograft rejection

The introduction of cyclosporine A (CyA) into the immunosuppressive therapy has significantly improved the results of heart transplantation (HTX). Its nephrotoxicity and hepatotoxicity, however, often limit the perioperative and postoperative use of this drug. The purpose of this retrospective study was to evaluate the effect of early postoperative CyA blood levels on the incidence of early as well as late cardiac rejection and patients' survival. Between October 1985 and June 1991, HTX was performed in 311 patients. Standard immunosuppression consisted of azathioprine (1-2 mg/kg), prednisolone (0.5 to 0.1 mg/kg) and CyA. Rabbit-antithymocyte-globulin (RATG - 1.5 mg/kg) was administered for the first 4 days postoperatively. Moderate rejection was treated with 3 x 500 mg methylprednisolone, severe rejection with RATG (1.5 mg/kg three times a day). Patients were excluded from this study because of a positive cross-matching, early death unrelated to rejection or alternate forms of immunosuppression (n = 111). Follow-up was complete in 200 patients (mean age 44 +/- 11; 18 female, 182 male; 204,233 patient days) with a total of 5380 biopsies. The cohort was divided into group I (no CyA for day 0 to 2; n = 108) and group II (CyA during day 0 to 2; n = 92) according to the onset of CyA therapy. In 101 patients (group A) the mean CyA blood level was less than 150 ng/ml from day 0 to 14 and in 99 patients more than 150 ng/ml (group B).(ABSTRACT TRUNCATED AT 250 WORDS)

Eotaxin/CCL11 expression by infiltrating macrophages in rat heart transplants during ongoing acute rejection

Eotaxin/CCL11 chemokine is expressed in different organs, including the heart, but its precise cellular origin in the heart is unknown. Eotaxin is associated with Th2-like responses and exerts its chemotactic effect through the chemokine receptor-3 (CCR3), which is also expressed on mast cells (MC). The aim of our study was to find the cellular origin of eotaxin in the heart, and to assess whether expression is changing during ongoing acute heart transplant rejection, indicating a correlation with mast cell infiltration which we observed in a previous study. In a model of ongoing acute heart transplant rejection in the rat, we found eotaxin mRNA expression within infiltrating macrophages, but not in mast cells, by in situ-hybridization. A five-fold increase in eotaxin protein in rat heart transplants during ongoing acute rejection was measured on day 28 after transplantation, compared to native and isogeneic control hearts. Eotaxin concentrations in donor hearts on day 28 after transplantation were significantly higher compared to recipient hearts, corroborating an origin of eotaxin from cells within the heart, and not from the blood. The quantitative comparison of eotaxin mRNA expression between native hearts, isografts, and allografts, respectively, revealed no statistically significant difference after transplantation, probably due to an overall increase in the housekeeping gene's 18S rRNA during rejection. Quantitative RT-PCR showed an increase in mRNA expression of CCR3, the receptor for eotaxin, during ongoing acute rejection of rat heart allografts. Although a correlation between increasing eotaxin expression by macrophages and mast cell infiltration is suggestive, functional studies will elucidate the role of eotaxin in the process of ongoing acute heart transplant rejection.

ABO blood group incompatible haematopoietic stem cell transplantation and xenograft rejection

The current organ shortage in transplantation medicine stimulates the exploration of new strategies to expand the donor pool including the utilisation of living donors, ABO-incompatible grafts, and xenotransplantation. Preformed natural antibodies (Ab) such as anti-Gal or anti-A/B Ab mediate hyperacute graft rejection and thus represent a major hurdle to the employment of such strategies. In contrast to solid organ transplantation (SOT), ABO blood group incompatibilities are of minor importance in haematopoietic stem cell transplantation (HSCT). Thus, ABO incompatible HSCT may serve as an in vivo model to study carbohydrate antigen (Ag)-mismatched transplantations such as ABO-incompatible SOT or the effect of preformed Ab against Gal in xenotransplantation. This mini-review summarises our clinical and experimental studies performed with the support of the Swiss National Science Foundation program on Implants and Transplants (NFP-46). Part 1 describes data on the clinical outcome of ABO-incompatible HSCT, in particular the incidence of several immunohaematological complications, acute graft-versus-host-disease (GvHD), and the overall survival. Part 2 summarises the measurements of anti-A/B Ab in healthy blood donors and ABO-incompatible HSCT using a novel flow cytometry based method and the potential mechanisms responsible for the loss of anti-A/B Ab observed following minor ABO-incompatible HSCT, ie the occurrence of humoral tolerance. Part 3 analyses the potential of eliminating Gal expression as well as specific complement inhibitors such as dextran sulfate and synthetic tyrosine analogues to protect porcine endothelial cells from xenoreactive Ab-mediated damage in vitro and in a hamster-to-rat heart transplantation model. In conclusion, due to similarities of the immunological hurdles of ABO incompatible transplantations and xenotransplantation, the knowledge obtained from both fields might lead to new strategies to overcome humoral rejection in transplantation.

Endothelial cell protection by dextran sulfate: a novel strategy to prevent acute vascular rejection in xenotransplantation

We showed recently that low molecular weight dextran sulfate (DXS) acts as an endothelial cell (EC) protectant and prevents human complement- and NK cell-mediated cytotoxicity towards porcine cells in vitro. We therefore hypothesized that DXS, combined with cyclosporine A (CyA), could prevent acute vascular rejection (AVR) in the hamster-to-rat cardiac xenotransplantation model. Untreated, CyA-only, and DXS-only treated rats rejected their grafts within 4-5 days. Of the hearts grafted into rats receiving DXS in combination with CyA, 28% survived more than 30 days. Deposition of anti-hamster antibodies and complement was detected in long-term surviving grafts. Combined with the expression of hemoxygenase 1 (HO-1) on graft EC, these results indicate that accommodation had occurred. Complement activity was normal in rat sera after DXS injection, and while systemic inhibition of the coagulation cascade was observed 1 h after DXS injection, it was absent after 24 h. Moreover, using a fluorescein-labeled DXS (DXS-Fluo) injected 1 day after surgery, we observed a specific binding of DXS-Fluo to the xenograft endothelium. In conclusion, we show here that DXS + CyA induces long-term xenograft survival and we provide evidence that DXS might act as a local EC protectant also in vivo.

Xenograft rejection: IgG1, complement and NK cells team up to activate and destroy the endothelium

Acute vascular rejection represents a formidable barrier to clinical xenotransplantation and it is known that this type of rejection can also be initiated by xenoreactive antibodies that have limited complement-activating ability. Using a sophisticated mouse model, a recent study has provided in vivo evidence for the existence of an IgG(1)-mediated vascular rejection, which uniquely depends on both the activation of complement and interactions with FcgammaRIII on natural killer (NK) cells.

Quantitative myocardial contrast echocardiography: a new method for the non-invasive detection of chronic heart transplant rejection

Chronic heart transplant rejection, i.e. cardiac allograft vasculopathy (CAV) is a major adverse prognostic factor after heart transplantation (HTx). This study tested the hypothesis that the relative myocardial blood volume (rBV) as quantified by myocardial contrast echocardiography accurately detects severe CAV as defined by coronary intravascular ultrasound (IVUS).

Penetrating keratoplasty and graft rejection in eight horses

The aim of this study was to describe long-term follow-up and difference in immune reactions in the tear film following penetrating keratoplasty (PK) in horses when differently preserved corneas were utilised. This report describes for the first time the use of corneal grafts preserved in tissue culture media in equine PK. Eight experimental horses with normal eyes were included and freshly harvested, frozen or preserved corneal grafts were used for the PK. The graft-taking technique and storage, PK surgery, postoperative treatments and complications are described. The mean postoperative follow-up time was 286 days. Tear film samples taken before and periodically after surgery were measured for IgM, IgG and IgA contents by direct ELISA. All grafts were incorporated into the donor horse but were rejected to some degree. The differently harvested corneal grafts healed in the same manner and looked similar. Preoperatively, the clear corneas meant low risk for graft failure, and the fresh or stored tissues provided intact endothelium, although there were no clear graft sites postoperatively. The presence of IgA, IgG and IgM was demonstrated in the tear film from the early postoperative period. IgG levels were lower than IgA or IgM and had a constant baseline in every case, as IgA and IgM had great variability with time and an individual pattern in each eye.

Type I hypersensitivity and its pharmacological modulation in {\it Trichinella\/}-induced intestinal fluid secretion and rapid rejection of the parasite in immunized rats

Studies were performed to test the hypothesis that type I hypersensitivity underlies worm induced intestinal fluid secretion and the rapid rejection of Trichinella spiralis from immunized rats, and the two events may be related in a cause-effect manner.^ Two approaches were taken. One was to determine whether inhibition of anaphylaxis-mediated Cl$\sp{-}$ and fluid secretion accompanying a secondary infection impedes worm rejection from immune hosts. The other was to determine whether induction of intestinal fluid secretion in nonimmune hosts interfered with worm establishment. In both studies, fluid secretion was measured volumetrically 30 min after a challenge infection and worms were counted.^ In immunized rats indomethacin did not affect the worm-induced fluid secretion when used alone, despite inhibiting mucosal prostaglandin synthesis. Fluid secretion was reduced by treatment with diphenhydramine and further reduced by the combination of diphenhydramine and indomethacin. The paradoxical effects of indomethacin when used alone compared with its coadministration with diphenhydramine is explained by the enhancing effect of indomethacin on histamine release. Abolishing net fluid secretion in these studies had no effect on rapid worm rejection in immune hosts.^ Worm establishment was reduced in recipients of immune serum containing IgE antibodies. Net intestinal fluid secretion induced in normal rats by PGE$\sb2$, cholera toxin, or hypertonic mannitol solution had no effect on worm establishment compared with untreated controls.^ In a related experiment, worm-induced intestinal fluid secretion and worm rejection in immune rats were partially blocked by concurrent injection with 5-HT$\sb2$ and 5-HT$\sb3$ blockers (Ketanserin and MDL-72222), suggesting that 5-HT is involved. This possible involvement was supported in that treatment of nonimmune rats with 5-HT significantly inhibited worm establishment in the intestine.^ Results indicate that anaphylaxis is the basis for both worm-induced intestinal fluid secretion and rapid rejection of T. spiralis in immune rats, but these events are independent of one another. 5-HT is a possible mediator of worm rejection, however, its mechanism of action is related to something other than fluid secretion. ^

Swiss Shock: Minaret Rejection, European Values, and the Challenge of Tolerant neutrality

In 2009 Switzerland, for long an apparent beacon of European toleration and neutrality, voted to ban the erection of minarets. Internal religious matters are normally dealt with at the regional or local level – not at the level of the Swiss national parliament, although the state does seek to ensure good order and peaceful relations between different faith communities. Indeed, the freedom of these communities to believe and function publicly is enshrined in law. However, as a matter of national policy, now constitutionally embedded, one religious group, the Muslim group, is not permitted to build their distinctive religious edifice, the minaret. Switzerland may have joined the rest of Europe with respect to engaging the challenge of Islamic presence to European identity and values, but the rejection of a symbol of the presence of one faith – in this case, Islamic – by a society that is otherwise predominantly secular, pluralist, and of Christian heritage, poses significant concerns. How and why did this happen? What are the implications? This paper will discuss some of the issues involved, concluding the ban is by no means irreversible. Tolerant neutrality may yet again be a leitmotif of Swiss culture and not just of foreign policy.

A Comparative Analysis of Bronchial Stricture After Lung Transplantation in Recipients With and Without Early Acute Rejection

BACKGROUND: Risk factors and outcomes of bronchial stricture after lung transplantation are not well defined. An association between acute rejection and development of stricture has been suggested in small case series. We evaluated this relationship using a large national registry. METHODS: All lung transplantations between April 1994 and December 2008 per the United Network for Organ Sharing (UNOS) database were analyzed. Generalized linear models were used to determine the association between early rejection and development of stricture after adjusting for potential confounders. The association of stricture with postoperative lung function and overall survival was also evaluated. RESULTS: Nine thousand three hundred thirty-five patients were included for analysis. The incidence of stricture was 11.5% (1,077/9,335), with no significant change in incidence during the study period (P=0.13). Early rejection was associated with a significantly greater incidence of stricture (adjusted odds ratio [AOR], 1.40; 95% confidence interval [CI], 1.22-1.61; p<0.0001). Male sex, restrictive lung disease, and pretransplantation requirement for hospitalization were also associated with stricture. Those who experienced stricture had a lower postoperative peak percent predicted forced expiratory volume at 1 second (FEV1) (median 74% versus 86% for bilateral transplants only; p<0.0001), shorter unadjusted survival (median 6.09 versus 6.82 years; p<0.001) and increased risk of death after adjusting for potential confounders (adjusted hazard ratio 1.13; 95% CI, 1.03-1.23; p=0.007). CONCLUSIONS: Early rejection is associated with an increased incidence of stricture. Recipients with stricture demonstrate worse postoperative lung function and survival. Prospective studies may be warranted to further assess causality and the potential for coordinated rejection and stricture surveillance strategies to improve postoperative outcomes.

Cytomegalovirus Serology and Replication Remain Associated With Solid Organ Graft Rejection and Graft Loss in the Era of Prophylactic Treatment

BACKGROUND Cytomegalovirus (CMV) replication has been associated with more risk for solid organ graft rejection. We wondered whether this association still holds when patients at risk receive prophylactic treatment for CMV. METHODS We correlated CMV infection, biopsy-proven graft rejection, and graft loss in 1,414 patients receiving heart (n=97), kidney (n=917), liver (n=237), or lung (n=163) allografts reported to the Swiss Transplant Cohort Study. RESULTS Recipients of all organs were at an increased risk for biopsy-proven graft rejection within 4 weeks after detection of CMV replication (hazard ratio [HR] after heart transplantation, 2.60; 95% confidence interval [CI], 1.34-4.94, P<0.001; HR after kidney transplantation, 1.58; 95% CI, 1.16-2.16, P=0.02; HR after liver transplantation, 2.21; 95% CI, 1.53-3.17, P<0.001; HR after lung transplantation, 5.83; 95% CI, 3.12-10.9, P<0.001. Relative hazards were comparable in patients with asymptomatic or symptomatic CMV infection. The CMV donor or recipient serological constellation also predicted the incidence of graft rejection after liver and lung transplantation, with significantly higher rates of rejection in transplants in which donor or recipient were CMV seropositive (non-D-/R-), compared with D- transplant or R- transplant (HR, 3.05; P=0.002 for liver and HR, 2.42; P=0.01 for lung transplants). Finally, graft loss occurred more frequently in non-D- or non-R- compared with D- transplant or R- transplant in all organs analyzed. Valganciclovir prophylactic treatment seemed to delay, but not prevent, graft loss in non-D- or non-R- transplants. CONCLUSION Cytomegalovirus replication and donor or recipient seroconstellation remains associated with graft rejection and graft loss in the era of prophylactic CMV treatment.