Cemiplimab for advanced cutaneous squamous cell carcinoma in kidney transplant recipients.

Background: Kidney transplant recipients (KTR) are at increased risk of cancer due to chronic immunosuppression. Non-melanoma skin cancer has an excess risk of approximately 250 times higher than the general population. Moreover, in solid organ transplant recipients (SOTR) these cancers have a more aggressive behavior, with an increased risk of metastasis and death. Cemiplimab, a human monoclonal IgG4 antibody against programmed cell death (PD-1) has shown considerable clinical activity in metastatic and locally advanced cutaneous squamous cell carcinoma (cSCC) in patients for whom no widely accepted standard of care exists. Cemiplimab has therefore been approved since 2018 for the treatment of advanced cSCC. However, data regarding the use of cemiplimab in SOTR and particularly in KTR are scarce and based on published case reports and small case series. In this study, we report on the real-life outcome of cemiplimab use in a Belgian cohort of seven KTR suffering from advanced cSCC. Objective: To report on the overall response rate (ORR) and safety of cemiplimab in KTR in Belgium. Results: Seven patients suffering from advanced cSCC, treated with cemiplimab, between 2018 and 2022, in Belgium were identified. Three patients were on corticosteroid monotherapy, one patient on tacrolimus monotherapy and three patients were on at least 2 immunosuppressants at start of cemiplimab. The ORR was 42.8%, stable disease was seen in 14.3% and progressive disease was found in 42.8% of the patients, respectively. The median administered number of cycles was 12, interquartile range (IQR) 25-75 [3.5 - 13.5]. All patients were treated with surgery before administration of cemiplimab, 71.4% received additional radiotherapy and only 1 patient was treated with chemotherapy prior to receiving cemiplimab. Biopsy-proven acute renal allograft rejection was observed in one patient, who eventually lost his graft function but showed a complete tumor response to treatment. Low grade skin toxicity was seen in one patient of the cohort. Conclusion: The present case series shows that the use of cemiplimab in KTR with advanced cSCC who failed to respond to previous surgery, chemo - and/or radiotherapy treatment is associated with an ORR of 42.8% with minimal risk of graft rejection (14.3%) and good tolerance.

Effect of donor nephrectomy time during circulatory-dead donor kidney retrieval on transplant graft failure.

BACKGROUND: When the blood supply ceases in a deceased organ donor, ischaemic injury starts. Kidneys are cooled to reduce cellular metabolism and minimize ischaemic injury. This cooling is slow and kidneys are lukewarm during nephrectomy. Smaller single-centre studies have shown that prolonged donor nephrectomy time decreases early kidney transplant function, but the effect on long-term outcome has never been investigated in large multicentre cohort studies. METHODS: The relationship between donor nephrectomy time and death-censored graft survival was evaluated in recipients of single adult-to-adult, first-time deceased-donor kidneys transplanted in the Eurotransplant region between 2004 and 2013. RESULTS: A total of 13 914 recipients were included. Median donor nephrectomy time was 51 (i.q.r. 39-65) min. Kidneys donated after circulatory death had longer nephrectomy times than those from brain-dead donors: median 57 (43-78) versus 50 (39-64) min respectively (P < 0·001). Donor nephrectomy time was independently associated with graft loss when kidneys were donated after circulatory death: adjusted hazard ratio (HR) 1·05 (95 per cent c.i. 1·01 to 1·09) per 10-min increase (P = 0·026). The magnitude of this effect was comparable to the effect of each hour of additional cold ischaemia: HR 1·04 (1·01 to 1·07) per h (P = 0·004). For kidneys donated after brain death, there was no effect of nephrectomy time on graft survival: adjusted HR 1·01 (0·98 to 1·04) per 10 min (P = 0·464). CONCLUSION: Prolonged donor nephrectomy time impairs graft outcome in kidneys donated after circulatory death. Keeping this short, together with efficient cooling during nephrectomy, might improve outcome.

ANTECEDENTES: La lesión por isquemia empieza en el momento que cesa la irrigación sanguínea del órgano donante. Para reducir el metabolismo celular y la lesión isquémica se reduce la temperatura de los riñones. Este enfriamiento es lento y los riñones se mantienen tibios durante la nefrectomía. Estudios unicéntricos con muestras pequeñas han demostrado que el tiempo de la nefrectomía del donante disminuye la función precoz del injerto renal, pero nunca se ha analizado su repercusión a largo plazo en grandes estudios multicéntricos. MÉTODOS: Se analizó la relación entre la duración de la nefrectomía del donante y la supervivencia del injerto en 13.914 adultos receptores de un primer riñón procedente de donante cadavérico adulto en la región de Eurotransplant entre los años 2004 y 2013. RESULTADOS: La mediana de duración de la nefrectomía del donante fue de 51 minutos (rango intercuartílico 39-65). En los riñones obtenidos en donantes a corazón parado la duración de la nefrectomía fue más prolongada que en los donantes en muerte cerebral (mediana 57 min (43-78 min) versus 50 min (39-64 min), P < 0,001). La duración de la nefrectomía en el donante se asoció de forma independiente con la pérdida del injerto (cociente de riesgos instantáneos, hazard ratio, HR, ajustado 1,05 por cada incremento de 10 minutos, i.c. del 95%: 1,01 a 1,09; P = 0,026) cuando los riñones se obtuvieron en donantes en parada cardíaca. La magnitud de este efecto fue comparable al efecto de cada hora adicional de isquemia fría (1,04, i.c. 95% 1,01-1,07, P = 0,004). En los riñones obtenidos de donantes en muerte cerebral, la duración de la nefrectomía no influyó en la supervivencia del injerto (HR ajustada 1,01 por aumento de 10 min, i.c. del 95%: 0,98 a 1,04). CONCLUSIÓN: La duración de la nefrectomía en donantes a corazón parado afecta la función de los injertos trasplantados. Reducir esta duración y disponer de un sistema de enfriamiento eficiente durante la nefrectomía podría mejorar los resultados.

Monoclonal gammopathy of renal significance (MGRS) histopathologic classification, diagnostic workup, and therapeutic options.

Monoclonal gammopathy of renal significance (MGRS) includes all kidney disorders caused by a monoclonal protein (M-protein) secreted by a small plasma cell clone or other B-cell clones in patients who do not meet the diagnostic criteria for multiple myeloma or other B-cell malignancies. The underlying disorder in patients with MGRS is generally consistent with monoclonal gammopathy of undetermined significance (MGUS). MGRS-associated kidney disorders are various and the list is still expanding. The kidney disorders can manifest as glomerular diseases, tubulopathies, and vascular involvement with varying clinical presentations. Diagnosis is often challenging because of the wide spectrum of MGRS, and it is difficult to establish a pathogenic link between the presence of the M-protein or serum free light chains and kidney diseases; further complicating accurate diagnosis is the high incidence of MGUS and/or kidney disorders, independent of MGRS, in elderly patients. However, MGRS can significantly impair kidney function. Because treatment can stop and also reverse kidney disease, early recognition is of great importance. A combined haematologic and nephrologic approach is crucial to establish the causative role of the M-protein in the pathogenesis of kidney disease. Clone-directed therapy, which may include autologous stem cell transplantation in eligible patients, often results in improved outcomes. In this review, we discuss the histopathologic classification of MGRS lesions, provide a renal and haematologic diagnostic workup, discuss treatment options for MGRS, and introduce a Benelux MGRS Working Group.

Myeloid-derived suppressor cells in lymphoma: The good, the bad and the ugly.

Lymphomas cause significant morbidity and mortality worldwide. A substantial number of patients ultimately relapse after standard treatment. However, the efficacy of these therapies can be counteracted by the patients' immune system, more specifically by myeloid-derived suppressor cells (MDSC). MDSC are a heterogeneous group of immature myeloid cells that suppress the innate and adaptive immune system via different mechanisms and accumulate under pathological conditions, such as cancer. MDSC play a role in the induction and progression of cancer and immune evasion. Increased numbers of MDSC have been reported in different lymphoma subtypes and are associated with a poor clinical outcome. This review aims to clarify the role of MDSC and their working mechanism in different lymphoma subtypes. Furthermore, the effect of MDSC on immunotherapies will be discussed.

The duration of asystolic ischemia determines the risk of graft failure after circulatory-dead donor kidney transplantation: A Eurotransplant cohort study.

Circulatory death donor (DCD) kidney transplantations are steadily increasing. Consensus reports recommend limiting donor warm ischemia time (DWIT) in DCD donation, although an independent effect on graft outcome has not been demonstrated. We investigated death-censored graft survival in 18 065 recipients of deceased-donor kidney transplants in the Eurotransplant region: 1059 DCD and 17 006 brain-dead donor (DBD) kidney recipients. DWIT was defined as time from circulatory arrest until cold flush. DCD donation was an independent risk factor for graft failure (adjusted hazard ratio [HR] 1.28, 95% CI 1.10-1.46), due to an increased risk of primary nonfunction (62/1059 vs 560/17 006; P < .0001). With DWIT in the model, DCD donation was no longer a risk factor, demonstrating that DWIT explains the inferior graft survival of DCD kidneys. Indeed, DCD transplants with short DWIT have graft survival comparable to that of standard-criteria DBD transplants (P = .59). DWIT also associated with graft failure in DCDs (adjusted HR 1.20 per 10-minute increase, 95% CI 1.03-1.42). At 5 years after transplantation, graft failure occurred in 14 of 133 recipients (10.5%) with DWIT <10 minutes, 139 of 555 recipients (25.0%) with DWIT between 10 and 19 minutes, and 117 of 371 recipients (31.5%) with DWIT ≥20 minutes. These findings support the expert opinion-based guidelines to limit DWIT.

Diagnostic thresholds for free light chains in multiple myeloma depend on the assay used.

Leukemia accepted article preview online, 20 November 2017. doi:10.1038/leu.2017.335.

Origin of Enriched Regulatory T Cells in Patients Receiving Combined Kidney-Bone Marrow Transplantation to Induce Transplantation Tolerance.

We examined tolerance mechanisms in patients receiving HLA-mismatched combined kidney-bone marrow transplantation (CKBMT) that led to transient chimerism under a previously published nonmyeloablative conditioning regimen (Immune Tolerance Network study 036). Polychromatic flow cytometry and high-throughput sequencing of T cell receptor-ß hypervariable regions of DNA from peripheral blood regulatory T cells (Tregs) and CD4 non-Tregs revealed marked early enrichment of Tregs (CD3+ CD4+ CD25high CD127low Foxp3+ ) in blood that resulted from peripheral proliferation (Ki67+ ), possibly new thymic emigration (CD31+ ), and, in one tolerant subject, conversion from non-Tregs. Among recovering conventional T cells, central memory CD4+ and CD8+ cells predominated. A large proportion of the T cell clones detected in posttransplantation biopsy specimens by T cell receptor sequencing were detected in the peripheral blood and were not donor-reactive. Our results suggest that enrichment of Tregs by new thymic emigration and lymphopenia-driven peripheral proliferation in the early posttransplantation period may contribute to tolerance after CKBMT. Further, most conventional T cell clones detected in immunologically quiescent posttransplantation biopsy specimens appear to be circulating cells in the microvasculature rather than infiltrating T cells.

The Impact of Anastomosis Time During Kidney Transplantation on Graft Loss: A Eurotransplant Cohort Study.

Recent studies raised the concern that warm ischemia during completion of vascular anastomoses in kidney implantation harms the transplant, but its precise impact on outcome and its interaction with other risk factors remain to be established. We investigated the relationship between anastomosis time and graft survival at 5 years after transplantation in 13 964 recipients of deceased donor solitary kidney transplants in the Eurotransplant region. Anastomosis time was independently associated with graft loss after adjusting for other risk factors (adjusted hazard ratio [HR] 1.10 for every 10-min increase, 95% confidence interval [CI] 1.06-1.14; p < 0.0001), whereas it did not influence recipient survival (HR 1.00, 95% CI 0.97-1.02). Kidneys from donation after circulatory death (DCD) were less tolerant of prolonged anastomosis time than kidneys from donation after brain death (p = 0.02 for interaction). The additive effect of anastomosis time with donor warm ischemia time (WIT) explains this observation because DCD status was no longer associated with graft survival when adjusted for this summed WIT, and there was no interaction between DCD status and summed WIT. Time to create the vascular anastomoses in kidney transplantation is associated with inferior transplant outcome, especially in recipients of DCD kidneys.

The Leuven Immunomodulatory Protocol Promotes T-Regulatory Cells and Substantially Prolongs Survival After First Intestinal Transplantation.

Intestinal transplantation (ITx) remains challenged by frequent/severe rejections and immunosuppression-related complications (infections/malignancies/drug toxicity). We developed the Leuven Immunomodulatory Protocol (LIP) in the lab and translated it to the clinics. LIP consists of experimentally proven maneuvers, destined to promote T-regulatory (Tregs)-dependent graft-protective mechanisms: donor-specific blood transfusion (DSBT); avoiding high-dose steroids/calcineurin-inhibitors; and minimizing reperfusion injury and endotoxin translocation. LIP was tested in 13 consecutive ITx from deceased donors (2000-2014) (observational cohort study). Recipient age was 37 years (2.8-57 years). Five-year graft/patient survival was 92%. One patient died at 9 months due to aspergillosis, another at 12 years due to nonsteroidal anti-inflammatory drug-induced enteropathy. Early acute rejection (AR) developed in two (15%); late AR in three (23%); all were reversible. No chronic rejection (CR) occurred. No malignancies developed and estimated glomerular filtration rate remained stable post-Tx. At last follow-up (3.5 years [0.5-12.5 years]), no donor-specific antibodies were detected and 11 survivors were total parenteral nutrition free with a Karnofsky score >90% in 8 recipients (follow-up >1 years). A high frequency of circulating CD4+ CD45RA- Foxp3hi memory Tregs was found (1.8% [1.39-2.21]), comparable to tolerant kidney transplant (KTx) recipients and superior to stable immunosuppression (IS)-KTx, KTx with CR, and healthy volunteers. In this ITx cohort we show that DSBT in a low-inflammatory/pro-regulatory environment activates Tregs at levels similar to tolerant-KTx, without causing sensitization. LIP limits rejection under reduced IS and thereby prolongs long-term survival to an extent not previously attained after ITx.

The Emerging Role of DNA Methylation in Kidney Transplantation: A Perspective.

Allograft outcome depends on a range of factors, including donor age, the allo-immune response, ischemia-reperfusion injury, and interstitial fibrosis of the allograft. Changes in the epigenome, and in DNA methylation in particular, have been implicated in each of these processes, in either the kidney or other organ systems. This review provides a primer for DNA methylation analyses and a discussion of the strengths and weaknesses of current studies, but it is also a perspective for future DNA methylation research in kidney transplantation. We present exciting prospects for leveraging DNA methylation analyses as a tool in kidney biology research, and as a diagnostic or prognostic marker for predicting allograft quality and success. Topics discussed include DNA methylation changes in aging and in response to hypoxia and oxidative stress upon ischemia-reperfusion injury. Moreover, emerging evidence suggests that DNA methylation contributes to organ fibrosis and that systemic DNA methylation alterations correlate with the rate of kidney function decline in patients with chronic kidney disease and end-stage renal failure. Monitoring or targeting the epigenome could therefore reveal novel therapeutic approaches in transplantation and open up paths to biomarker discovery and targeted therapy.

The effect of anastomosis time on outcome in recipients of kidneys donated after brain death: a cohort study.

Whether warm ischemia during the time to complete the vascular anastomoses determines renal allograft function has not been investigated systematically. We investigated the effect of anastomosis time on allograft outcome in 669 first, single kidney transplantations from brain-dead donors. Anastomosis time independently increased the risk of delayed graft function (odds ratio per minute [OR] 1.05, 95% confidence interval [CI] 1.02-1.07, p < 0.001) and independently impaired allograft function after transplantation (p = 0.009, mixed-models repeated-measures analysis). In a subgroup of transplant recipients, protocol-specified biopsies at 3 months (n = 186), 1 year (n = 189), and 2 years (n = 153) were blindly reviewed. Prolonged anastomosis time independently increased the risk of interstitial fibrosis and tubular atrophy on these protocol-specified biopsies posttransplant (p < 0.001, generalized linear models). In conclusion, prolonged anastomosis time is not only detrimental for renal allograft outcome immediately after transplantation, also longer-term allograft function and histology are affected by the duration of this warm ischemia.

Macrochimerism in Intestinal Transplantation: Association With Lower Rejection Rates and Multivisceral Transplants, Without GVHD.

Blood chimerism has been reported sporadically among visceral transplant recipients, mostly in association with graft-vs-host disease (GVHD). We hypothesized that a higher degree of mixed chimerism would be observed in multivisceral (MVTx) than in isolated intestinal (iITx) and isolated liver transplant (iLTx) recipients, regardless of GVHD. We performed a longitudinal prospective study investigating multilineage blood chimerism with flow cytometry in 5 iITx and 4 MVTx recipients up to one year posttransplant. Although only one iITx patient experienced GVHD, T cell mixed chimerism was detected in 8 out of 9 iITx/MVTx recipients. Chimerism was significantly lower in the four subjects who displayed early moderate to severe rejection. Pre-formed high-titer donor-specific antibodies, bound in vivo to the circulating donor cells, were associated with an accelerated decline in chimerism. Blood chimerism was also studied in 10 iLTx controls. Among nonsensitized patients, MVTx recipients exhibited greater T and B cell chimerism than either iITx or iLTx recipients. Myeloid lineage chimerism was present exclusively among iLTx and MVTx (6/13) recipients, suggesting that its presence required the hepatic allograft. Our study demonstrates, for the first time, frequent T cell chimerism without GVHD following visceral transplantation and a possible relationship with reduced rejection rate in MVTx recipients.

Renal effects of molecular targeted therapies in oncology: a review by the Cancer and the Kidney International Network (C-KIN).

A number of cancer therapy agents are cleared by the kidney and may affect renal function, including cytotoxic chemotherapy agents, molecular targeted therapies, analgesics, antibiotics, radiopharmaceuticals and radiation therapy, and bone-targeted therapies. Many of these agents can be nephrotoxic, including targeted cancer therapies. The incidence, severity, and pattern of renal toxicities may vary according to the respective target of the drug. Here, we review the renal effects associated with a selection of currenty approved targeted cancer therapies, directed to vascular endothelial growth factor or VEGF receptor(s) (VEGF/VEGFR), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor2 (HER2), BRAF, anaplastic lymphoma kinase (ALK), programmed cell death protein-1 or its ligand (PD-1/PDL-1), receptor activator of nuclear factor kappa-B ligand (RANKL), and mammalian target of rapamycin (mTOR). The early diagnosis and prompt treatment of these renal alterations are essential in the daily practice where molecular targeted therapies have a definitive role in the armamentarium used in many cancers.

Long-term results in recipients of combined HLA-mismatched kidney and bone marrow transplantation without maintenance immunosuppression.

We report here the long-term results of HLA-mismatched kidney transplantation without maintenance immunosuppression (IS) in 10 subjects following combined kidney and bone marrow transplantation. All subjects were treated with nonmyeloablative conditioning and an 8- to 14-month course of calcineurin inhibitor with or without rituximab. All 10 subjects developed transient chimerism, and in seven of these, IS was successfully discontinued for 4 or more years. Currently, four subjects remain IS free for periods of 4.5-11.4 years, while three required reinstitution of IS after 5-8 years due to recurrence of original disease or chronic antibody-mediated rejection. Of the 10 renal allografts, three failed due to thrombotic microangiopathy or rejection. When compared with 21 immunologically similar living donor kidney recipients treated with conventional IS, the long-term IS-free survivors developed significantly fewer posttransplant complications. Although most recipients treated with none or two doses of rituximab developed donor-specific antibody (DSA), no DSA was detected in recipients treated with four doses of rituximab. Although further revisions of the current conditioning regimen are planned in order to improve consistency of the results, this study shows that long-term stable kidney allograft survival without maintenance IS can be achieved following transient mixed chimerism induction.

Henoch-Schönlein Purpura complicated with major gastro-intestinal hemorrhage.

We report a case of Henoch-Schönlein Purpura in a 83-year old patient. The patient presented with a purpuric rash and arthralgia. During admission, he developed hematochezia and acute kidney injury. Because of protracted gastro-intestinal bleeding after initiating therapy with methylprednisolone and ileocaecal resection, azathioprine was started. Gastro-intestinal bleeding resolved, and renal function normalized. We present the clinical and pathological findings of Henoch-Schönlein Purpura, focusing on gastro-intestinal manifestations.

Chronic wounds in a kidney transplant recipient with moderate renal impairment.

Calcific uremic arteriolopathy (CUA) or calciphylaxis is a condition predominantly observed in patients with end-stage kidney disease characterized by small vessel calcification, intimal proliferation, endovascular fibrosis and intravascular thrombosis causing down-stream infarction predominantly of skin resulting in extremely painful necrotic ulceration. Several interventions have been proposed in an attempt to attenuate the high mortality associated with CUA. One of the most promising therapeutic approaches is the administration of sodium thiosulfate which is able to chelate cations such as calcium and in this way possibly dissolving tissue calcium deposits into more hydrophilic calcium thiosulfate. Due to the scarcity of reports of CUA patients treated with sodium thiosulfate the safety profile of this drug is not (well) established at this moment especially in patients not receiving kidney replacement therapy. Here, we describe a case of a kidney transplant recipient with CUA and moderately declined kidney function who was treated with sodium thiosulfate and developed important hypernatremia and high anion gap acidosis necessitating significant reduction in dosing.

Acute renal endothelial injury during marrow recovery in a cohort of combined kidney and bone marrow allografts.

An idiopathic capillary leak syndrome ('engraftment syndrome') often occurs in recipients of hematopoietic cells, manifested clinically by transient azotemia and sometimes fever and fluid retention. Here, we report the renal pathology in 10 recipients of combined bone marrow and kidney allografts. Nine developed graft dysfunction on day 10-16 and renal biopsies showed marked acute tubular injury, with interstitial edema, hemorrhage and capillary congestion, with little or no interstitial infiltrate (≤10%) and marked glomerular and peritubular capillary (PTC) endothelial injury and loss by electron microscopy. Two had transient arterial endothelial inflammation; and 2 had C4d deposition. The cells in capillaries were primarily CD68(+) MPO(+) mononuclear cells and CD3(+) CD8(+) T cells, the latter with a high proliferative index (Ki67(+) ). B cells (CD20(+) ) and CD4(+) T cells were not detectable, and NK cells were rare. XY FISH showed that CD45(+) cells in PTCs were of recipient origin. Optimal treatment remains to be defined; two recovered without additional therapy, six were treated with anti-rejection regimens. Except for one patient, who later developed thrombotic microangiopathy and one with acute humoral rejection, all fully recovered within 2-4 weeks. Graft endothelium is the primary target of this process, attributable to as yet obscure mechanisms, arising during leukocyte recovery.

Subclinical GvHD in non-irradiated F1 hybrids: severe lymphoid-tissue GvHD causing prolonged immune dysfunction.

GvHD is an important complication of allogeneic hematopoietic SCT. Parent-in-F1 models are frequently used to study GvHD immunobiology; the characteristics of parent-in-F1 GvHD vary between strain combinations and induction protocols. Here, we observed that a high-dose challenge of non-irradiated B6DBA2F1 and B6SJLF1 recipients with C57BL/6 splenocytes left the majority of recipients clinically healthy, while inducing progressive high-grade donor T-cell chimerism. We investigated this previously undescribed pattern of parent-in-F1 T-cell alloreactivity and studied the effect of serial parental splenocyte infusions on epithelial and lymphohematopoietic tissues. The majority of recipients of 4 weekly splenocyte infusions showed long-term survival with gradual establishment of high-grade donor chimerism and without any signs of epithelial-tissue GvHD. A minority of recipients showed BM failure type of GvHD and, respectively, graft rejection. Moreover, long-term F1 chimeras showed protracted pancytopenia, and in peripheral lymphoid tissues severe lymphopenia and near-complete eradication of APCs and dysfunction in antigen-presenting capacity in remaining APC. Hematopoiesis and lymphoid tissue composition recovered only after multilineage donor chimerism had established. In conclusion, we report on a novel type of parent-in-F1 hybrid GvHD, where a cumulative high dose of C57BL/6 parental splenocytes in non-irradiated F1 mice induces subclinical but severe hematolymphoid-tissue GvHD, causing prolonged immuno-incompetence.

Allogeneic bone marrow transplantation and donor lymphocyte infusion in a mouse model of irradiation-induced myelodysplastic/myeloproliferation syndrome (MD/MPS): evidence for a graft-versus-MD/MPS effect.

The role of graft-versus-malignancy reactivity in the effects of allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusion (DLI) for myelodysplastic syndromes is as yet not well established. Clinical data are limited and animal models are scarce. Here, we report on the effects of allogeneic bone marrow transplantation (alloBMT) and DLI in a novel model of irradiation-induced murine myelodysplastic/myeloproliferation syndrome (MD/MPS). Total body irradiation with 8.5 Gy in SJL/J mice gave rise to a lethal wasting syndrome in 60% of mice, characterized by 1 degrees normocellular bone marrow with dysplastic features in erythroid, myeloid and megakaryocytic cell lineages, 2 degrees lymphosplenomegaly with spleens harboring a prominent extramedullary hematopoiesis with erythroid, myeloid and megakaryocytic lineages exhibiting dysplastic features, and foci of dysplastic hematomyelopoiesis in the liver, 3 degrees peripheral thrombocytopenia and 4 degrees evidence of disseminated infection or leukemic transformation in selected animals. This clinicopathological picture was consistent with a murine form of MD/MPS. Syngeneic or allogeneic (BALB/c) T cell-depleted BMT could not prevent the occurrence of lethal MD/MPS. In contrast, DLI at weeks 2-4 after BMT led to restoration of the dysbalanced hematomyelopoiesis. However, severe DLI-induced acute graft-versus-host disease occurred, precluding a survival advantage. We present evidence of the existence of a post-alloBMT DLI-induced graft-versus-MD/MPS effect in murine irradiation-induced MD/MPS.

Xenotransplantation: where are we in 2008?

Xenotransplantation holds promise to solve the ever increasing shortage of donor organs for allotransplantation. In the last 2 decades, major progress has been made in understanding the immunobiology of pig-into-(non)human primate transplantation and today we are on the threshold of the first clinical trials. Hyperacute rejection, which is mediated by pre-existing anti-alpha Gal xenoreactive antibodies, can in non-human primates be overcome by complement- and/or antibody-modifying interventions. A major step forward was the development of genetically engineered pigs, either transgenic for human complement regulatory proteins or deficient in the alpha1,3-galactosyltranferase enzyme. However, several other immunologic and nonimmunologic hurdles remain. Acute vascular xenograft rejection is mediated by humoral and cellular mechanisms. Elicited xenoreactive antibodies play a key role. In addition to providing B cell help, xenoreactive T cells may directly contribute to xenograft rejection. Long-term survival of porcine kidney- and heart xenografts in non-human primates has been obtained but required severe T and B cell immunosuppression. Induction of xenotolerance, e.g. through mixed hematopoietic chimerism, may represent the preferred approach, but although proof of principle has been delivered in rodents, induction of pig-to-non-human primate chimerism remains problematic. Finally, it is now clear that innate immune cells, in particular macrophages and natural killer cells, can mediate xenograft destruction, the determinants of which are being elucidated. Chronic xenograft rejection is not well understood, but recent studies indicate that non-immunological problems, such as incompatibilities between human procoagulant and pig anticoagulant components may play an important role. Here, we give a comprehensive overview of the currently known obstacles to xenografting: immune and non-immune problems are discussed, as well as the possible strategies that are under development to overcome these hurdles.