Sequential metabolic studies of pancreas allograft function in type 1 diabetic recipients.

We have previously shown that the loss of acute first phase insulin secretion precedes pancreas allograft rejection and development of glucose intolerance in Type 1 diabetic patients. In order to examine whether there is a progressive loss of phases of insulin secretion and beta-cell function in technically successful pancreas transplants during the first year, we measured glucose, insulin, and C-peptide responses to physiological (mixed meal) and pharmacological (IV glucose and IV glucagon) stimulation in 27 glucose-tolerant, insulin-independent allograft recipients at 3, 6, and 12 months. Mean +/- SE fasting serum glucose levels were normalized throughout the study period. Postprandial serum glucose profiles tended to increase by 12 months compared to 3 and 6 months, although peak glucose levels were not statistically different. Following pancreas transplantation, basal serum insulin levels were high at 3 months (163 +/- 17 pM), 6 months (165 +/- 22 pM), and 12 months (248 +/- 54 pM, p = NS) in the Type 1 diabetic pancreas allograft recipients when compared to normal (25 +/- 3 pM). We observed slight elevations in postprandial insulin and C-peptide profiles at 12 months compared to 3 and 6 months. Following IV glucose and glucagon stimulation, serum insulin and C-peptide levels as well as phases of insulin release did not differ over the 12-month study period. Similarly, the glucose decay constant (KG) was nearly identical at 3, 6, and 12 months. In summary, 1 year following successful whole cadaveric, heterotopic pancreas transplantation in Type 1 diabetic recipients, fasting serum glucose remains normalized, while postprandial glucose tends to rise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transplantation and the problems afterward including coronary vasculopathy

The clinical success of cardiac transplantation requires clinical cardiologists to become familiar with care of the post-transplant patient. This review emphasizes five major post-transplant problems: (1) infection/immunosuppression, (2) metabolic problems, (3) post-transplant hypertension, (4) exercise intolerance, and (5) graft coronary disease. The evolution of these problems after transplantation is emphasized, so that clinical cardiologists and internists sharing the management of these patients can develop a context in which to work.     

Tacrolimus with Mycophenolate Mofetil (MMF) or Sirolimus vs. Cyclosporine with MMF in Cardiac Transplant Patients: 1-Year Report

The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of >/=3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer >/=3A rejections or hemodynamic compromise rejections and an improved side-effect profile.     

Acute Cellular Rejection Predominated by Monocytes Is a Severe Form of Rejection in Human Renal Recipients With or Without Campath-1H (Alemtuzumab) Induction Therapy

Campath-1H has been used successfully for induction and has resulted in a low rate of acute cellular rejection (ACR) in renal transplantation in combination with various postoperative immunosuppression regimens. This study was undertaken to investigate the extent of monocyte involvement in ACR, with or without Campath-1H induction. We found that monocytes represented the majority of inflammatory cells in grades Ib or higher ACR, but not with Ia type of ACR, regardless of the status of Campath-1H induction. Cases of ACR, following Campath-1H induction, appear to demonstrate a 'pure form' of monocytic ACR, whereas monocytes were mixed with many other types of inflammatory cells in the cases of ACR in the absence of Campath-1H induction. In addition with Campath-1H induction, the cases of monocyte-predominant ACR were found to uniformly exhibit a good response to corticosteroid treatment. We conclude that monocyte-predominate ACR may represent a severe form of rejection, with or without Campath-1H treatment.     

Thrombus causing fatal left ventricular outflow tract obstruction in a heart transplant patient

A 60 year male, orthotopic heart transplant recipient developed a fatal left ventricular outflow obstruction secondary to thrombus at 38 months post transplant. Although he had episodes of mild to moderate rejection at 2 and 16 months post transplant, subsequent biopsies were negative and annual cardiac catheterizations showed mild left ventricular hypokinesis and normal coronary arteries. This case represents a catastrophic complication of transplant rejection and illustrates the problems with identifying rejection using current diagnostic methods.     

Phenotype of endomyocardial biopsy-derived T-lymphocyte cultures and chronic rejection after heart transplantation

Chronic rejection (CR) is a major problem in long-term survival in heart transplantation. We analysed whether the occurrence of CR correlates with the incidence of acute rejections (AR) or with characteristics of endomyocardial biopsy-derived cell cultures. CR was diagnosed by annual angiography and defined as all coronary vascular changes. One year after transplantation 24 of the 63 patients had CR (38%). The incidence of AR in CR + and CR — patients was comparable. The patients in both groups had similar individual median percentages of EMB-yielding cell cultures. During the first year the CR — patients had more cultures in which at least 60% of the cells were CD4 + T cells (50% vs 37%, P = 0.05), due to a stronger CD4 predominance in the first 6 months. In the second year the CD4 predominance in the patients diagnosed as CR + after 1 year tended to be higher (P = 0.08). The patients had comparable percentages of cultures predominated by CD8 + T cells, γδ T cells or NK cells, irrespective of the time interval. These results might indicate that CD4 + T lymphocytes play a dual role in the aetiology of CR.     

Mice aorta loop grafting： A new model which separate vascular rejection and neointimal formation in chronic rejection

To study the cause and mechanism of transplantation vasculopathy which characterized by accelerated graft arteriosclerosis ( AGA), we estabfished a mouse aorta graft model. Methods: A segment of thoracic aortas of B10. A (2R) mice were transplanted to C57BL/10 mice abdominal aorta by end to side anastomoses. The different time point collected grafts were analyzed by morphological, histochemical and electro microscopic methods. Results:Rejection was manifested as a concentric progressive destruction of the smooth muscle cells. In contrast, the endothelial inflammation and subsequent ncointimal proliferation characteristic of AGA was localized to the regions of turbulent flow, i.e. the junction of the graft with the recipient aorta. Conclusion: This model separates the processes of rejec-tion and neointimal formation which usually manifested together in the lesion of AGA, elucidate that different mecha-nisms control vascular rejection and neointimal formation in chronic rejection.     

NK Cells Rapidly Reject Allogeneic Bone Marrow in the Spleen Through a Perforin- and Ly49D-Dependent, but NKG2D-Independent Mechanism

We have used a sensitive and specific in vivo killing assay to monitor the kinetics, anatomic location and mechanisms controlling NK-mediated rejection of Balb/c bone marrow by C57BL/6 natural killer (NK) cells. We find that NK killing of fully allogeneic bone marrow is a rapid, highly efficient process, leading to substantial rejection of transplanted marrow within 6 h of transplant and elimination of 85% of the transplanted cells within 2 days. NK-mediated rejection occurred predominantly in the spleen, with sparing of rejection in the bone marrow and lymph nodes. Rejection was dependent on Perforin gene function, but was independent of interferon-gamma. Finally, rejection of Balb/c bone marrow by B6 NK cells required signaling through the Ly49D receptor, but occurred despite blockade of NKG2D, which distinguishes these results from previous studies using semiallogeneic transplant pairs. These results identify NK cells as highly active mediators of bone marrow rejection, and suggest that inhibiting NK function early during transplantation may increase the efficiency of engraftment and allow successful engraftment of limiting doses of donor bone marrow.     

Granulysin: A Novel Host Defense Molecule

Granulysin is a novel cationic molecule present in the granules of cytotoxic T lymphocytes and natural killer cells. Cytotoxic T lymphocytes have long been associated with graft destruction in transplant rejection. Recent studies implicate granulysin in cell-mediated cytotoxicity, chemoattraction, immune activation and as a potential diagnostic biomarker for transplant rejection.