Organ-Specific Patterns of Donor Antigen-Specific Hyporeactivity and Peripheral Blood Allogeneic Microchimerism in Lung, Kidney, and Liver Transplant Recipients1

Reinsmoen, Nancy L.; Jackson, Annette M.; McSherry, Cynthia; Ninova, Dora; Wiesner, Russell H.; Kondo, Mário; Krom, Ruud A.F.; Hertz, Marshall I.; Bolman, R. Morton; Matas, Arthur J.

doi:10.1097/00007890-199560120-00029

Cited by 65 publications

(34 citation statements)

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“…This postulation has been verified experimentally in rats (11)(12)(13)(14)(15) and in a mouse model of cardiac allotransplantation (16). Similar observations have also been made in long-surviving human lung (17,18) and renal (19) allograft recipients.…”

supporting

confidence: 67%

Abrogation of Chronic Rejection in a Murine Model of Aortic Allotransplantation by Prior Induction of Donor-Specific Tolerance1

et al. 1997

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Aortic allotransplantation in mice has been well established as a model of choice to study the evolvement of chronic rejection, the etiopathology of which is believed to be that of immune origin. This has prompted the postulation that prior induction of donor-specific tolerance would attenuate or abrogate the underlying events that culminate in posttransplant arteriosclerosis. To study the effects of donor-specific tolerance on chronic rejection, we performed orthotopic liver transplantation without immunosuppression in mice 30 days before aortic allotransplantation across C57Bl/10J (H2 b )→C3H (H2 k ) strain combinations (group III. Aortic allografting in syngeneic (group I; C3H→C3H) and allogeneic (group II, C57Bl/10J→C3H) animals served as controls. No morphological changes were evidenced in the transplanted aortas in group I animals. Contrarily, aortic allografts in group II animals underwent a self-limiting acute cellular rejection, which resolved completely and was succeeded by day 30 after transplantation by histopathological changes pathognomonic of chronic rejection. There was evidence for diffuse myointimal thickening, progressive concentric luminal narrowing, and patchy destruction of internal elastic membranes resulting in massive vascular obliteration by day 120 after transplantation. It was of interest that no arteriosclerotic changes were observed for the duration of follow-up (up to 120 days after transplantation) in transplanted aortas (liver donor-type) harvested from animals in group III. However, vasculopathy was prominent in third-party aortic grafts transplanted into tolerant recipients. Taken together, these data suggest that prior induction of tolerance abrogates the development of chronic rejection; this protection seems to be donor specific.The most common cause for late organ allograft failure is chronic rejection (CR * ); its incidence in organs surviving more than 5 years is up to 43%, 50%, and 60% for transplanted kidneys (1), lungs (2), and hearts (3), respectively. Conversely, its prevalence is much lower (3.6-16.8%) in long-surviving liver allografts (4). Although the factors underlying the changes pathognomonic of posttransplant obliterative vasculopathy are poorly understood, they nevertheless seem to be multifactorial (5-7). In addition to ischemia-reperfusion, allogeneic

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supporting

confidence: 67%

Abrogation of Chronic Rejection in a Murine Model of Aortic Allotransplantation by Prior Induction of Donor-Specific Tolerance1

et al. 1997

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“…Because freeze/thaw procedures routinely result in the loss of certain numbers of cells, it is reasonable to assume that a small population of donor cells could be brought below the detection threshold by the freezing procedure. In another comparison, donor cells were more frequently detected in blood samples from liver and intestine recipients than from the blood of kidney recipients [4,7,14]. As high as 3%-4% of CD45 + circulating leukocytes were donor-phenotype 30-days after intestinal and liver transplantation.…”

Section: Discussionmentioning

confidence: 96%

“…Frequency and level-The kind of allograft was a prime determinant of the frequency and level of early chimerism [4,13,14]. Between 30 and 60 days macrochimerism was detected by flow cytometry in 62% and 80% of liver and intestine recipients, respectively.…”

Section: Characteristics Of Peripheral Blood Chimerismmentioning

confidence: 99%

Four-color flow cytometric analysis of peripheral blood donor cell chimerism

et al. 2003

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Passenger leukocytes have been demonstrated to play significant roles in initiating and also regulating immune reactions after organ transplantation. Reliable techniques to detect donor leukocytes in recipients after organ transplantation are essential to analyze the role, function, and behavior of these leukocytes. In this report we describe a simple, reliable method to detect donor cells with low frequencies using peripheral blood samples. Detection of small numbers of major histocompatibility complex (MHC) mismatched cells was first studied using four-color flow cytometry in artificially created cell mixtures. By selecting the CD45 + population and simultaneous staining with several leukocyte lineage markers (CD3, CD4, CD8, CD56, and CD19), MHC-mismatched leukocytes were consistently detected in cell suspensions prepared from directly stained whole blood samples with a threshold sensitivity as low as 0.1%-0.2%. When the fresh peripheral blood mononuclear cells were separated by conventional Ficoll gradient purification, similar, but slightly lower levels of donor cells were detected. Blood samples obtained 1-5 months after liver, kidney, and intestine transplants revealed that the kind of organ allograft influenced levels and lineage pattern of the circulating donor cells. This procedure provided a simple and reliable method in determining early chimerism in transplant recipients. However, the detection of MHC-mismatched leukocytes of all lineages was much lower when frozen peripheral blood mononuclear cells were used.

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“…The utility of these tests has focused on predicting graft outcomes by correctly surmising that elevated precursor frequencies increase the likelihood and import of an alloimmune response. Reinsmoen et al (17) noted that reduced donor-specific precursor frequencies in kidney recipients correlates with lower rates of chronic allograft nephropathy (18). Patients with low limiting dilutional analysis values also enjoy improved long-term graft survival rates.…”

Section: Assays Of Lymphocyte Alloreactivity Andmentioning

confidence: 99%

Beyond Histology

Mannon¹,

Kirk²

2006

Clinical Journal of the American Society of Nephrology

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Kidney biopsy is the gold standard procedure for the assessment of allograft dysfunction. The differential diagnosis for both acute and chronic dysfunction can encompass a number of different causes, and a biopsy frequently can suggest a specific cause. However, many of these causes are difficult to distinguish on morphologic basis alone, and the information that is obtained from a biopsy is limited with regard to functional and prognostic importance. Additional methods therefore are needed to guide the diagnosis and the treatment of allograft dysfunction, and numerous methods have been studied. Potential markers include protein and gene expression profiles in the peripheral blood, the urine, and the graft itself, all compartments that are relevant to the alloimmune response. Recent comprehensive sequencing of the human genome has led to an unprecedented opportunity to develop these genetic and proteomic techniques, and ongoing evaluations of potential tests have led to an improved understanding of the complexity of immune responses. The future challenge for promising tests is validation in larger patient populations to facilitate their addition to the diagnostic armamentarium.

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Organ-Specific Patterns of Donor Antigen-Specific Hyporeactivity and Peripheral Blood Allogeneic Microchimerism in Lung, Kidney, and Liver Transplant Recipients1

Cited by 65 publications

References 0 publications

Abrogation of Chronic Rejection in a Murine Model of Aortic Allotransplantation by Prior Induction of Donor-Specific Tolerance1

Abrogation of Chronic Rejection in a Murine Model of Aortic Allotransplantation by Prior Induction of Donor-Specific Tolerance1

Four-color flow cytometric analysis of peripheral blood donor cell chimerism

Beyond Histology

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