Transplant arteriosclerosis: an enigmatic disease due to a misnomer

Solid organ transplantation across the allogeneic barrier, pioneered by Thomas Starzl, has by now become a common medical procedure. Unfortunately, the number of donor organs lost due to transplant arteriosclerosis (chronic rejection), remains significant and unchanged for decades. We argue that designation of transplant arteriosclerosis as chronic rejection, and its classification as a delayed long-lasting reaction of recipient immune effectors against donor alloantigens have given us a wrong impression that we have identified the necessary cause/pathogenesis of the tissue pathology. However, whatever treatment options we have in the anti-rejection toolbox, despite their success in treating classical rejection, do not work for the transplant arteriosclerosis. Yet, the scientific community has continued to conceptualize and approach the pathology within the alloimmunity model. Due to unproductive research from the alloimmunity and rejection perspective, the number of transplanted hearts lost due to this pathology today is almost the same as it was fifty years ago. We believe that this phenomenon falls under the rubric of linguistic relativity, and that language we chose to name the disease has restricted our cognitive ability to solve the problem. While the initial perception of the transplant arteriosclerosis as chronic rejection was logical and scientific, the subsequent experience revealed that such perception and approach have been fruitless, and likely are incorrect. Considering our tragic failure to prevent and treat the delayed arterial pathology of donor organs using all available knowledge on alloimmunity and rejection, we must finally disassociate the former from the latter. The only way to start this uncomfortable process is to change the words we are using; particularly, the words we chose to name the disease. We have to step out of the alloimmunity rejection box.Comment: 19 pages, 2 figure

Striking augmentation of hematopoietic cell chimerism in noncytoablated allogeneic bone marrow recipients by flt3 ligand and tacrolimus

The influence of granulocyte-macrophage colony-stimulating factor (GM- CSF) and the recently identified hematopoietic stem-progenitor cell mobilizing factor flt3 ligand (FL) on donor leukocyte microchimerism in noncytodepleted recipients of allogeneic bone marrow (BM) was compared. B10 mice (H2b) given 50 x 106 allogeneic (B10.BR [H2(k)]) BM cells also received either GM-CSF (4 μg/day s.c.), FL (10 μg/day i.p.), or no cytokine, with or without concomitant tacrolimus (formerly FK506; 2 mg/kg) from day 0. Chimerism was quantitated in the spleen 7 days after transplantation by both polymerase chain reaction (donor DNA [major histocompatibility complex class II; I-E(k)]) and immunohistochemical (donor [I-E(k+)] cell) analyses. Whereas GM-CSF alone significantly augmented (fivefold) the level of donor DNA in recipients' spleens, FL alone caused a significant (60%) reduction. Donor DNA was increased 10-fold by tacrolimus alone, whereas coadministration of GM-CSF and tacrolimus resulted in a greater than additive effect (28-fold increase). A much more striking effect was observed with FL + tacrolimus (>125-fold increase in donor DNA compared with BM alone). These findings were reflected in the relative numbers of donor major histocompatibility complex class II+ cells (many resembling dendritic cells) detected in spleens, although quantitative differences among the groups were less pronounced. Evaluation of cytotoxic T lymphocyte generation by BM recipients' spleen cells revealed that FL alone augmented antidonor immunity and that this was reversed by tacrolimus. Thus, although FL may potentiate antidonor reactivity in nonimmunosuppressed, allogeneic BM recipients, it exhibits potent chimerism-enhancing activity when coadministered with recipient immunosuppressive therapy. This property of FL may offer considerable potential for the augmentation of microchimerism, with therapeutic implications for organ allograft survival and tolerance induction

Portacaval shunt causes apoptosis and liver atrophy in rats despite increases in endogenous levels of major hepatic growth factors

Background/Aims: The response to the liver damage caused by portacaval shunt (PCS) is characterized by low-grade hyperplasia and atrophy. To clarify mechanisms of this dissociation, we correlated the expression of 'hepatotrophic factors' and the antihepatotrophic and proapoptotic peptide, transforming growth factor (TGF)-β, with the pathologic changes caused by PCS in rats. Methods: PCS was created by side-to-side anastomosis between the portal vein and inferior vena cava, with ligation of the hilar portal vein. Hepatic growth mediators were measured to 2 months. Results: The decrease in the liver/body weight ratio during the first 7 days which stabilized by day 15, corresponded to parenchymal cell apoptosis and increases in hepatic TGF-β concentration that peaked at 1.4 × baseline at 15 days before returning to control levels by day 30. Variable increases in the concentrations of growth promoters (hepatocyte growth factor, TGF-α and augmenter of liver regeneration) also occurred during the period of hepatocellular apoptosis. Conclusions: The development of hepatic atrophy was associated with changes in TGF-β concentration, and occurred despite increased expression of multiple putative growth promoters. The findings suggest that apoptosis set in motion by TGF-β constrains the amount of hepatocyte proliferation independently from control of liver volume. © 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved

Analysis of arterial intimal hyperplasia: review and hypothesis

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background: Despite a prodigious investment of funds, we cannot treat or prevent arteriosclerosis and restenosis, particularly its major pathology, arterial intimal hyperplasia. A cornerstone question lies behind all approaches to the disease: what causes the pathology? Hypothesis: I argue that the question itself is misplaced because it implies that intimal hyperplasia is a novel pathological phenomenon caused by new mechanisms. A simple inquiry into arterial morphology shows the opposite is true. The normal multi-layer cellular organization of the tunica intima is identical to that of diseased hyperplasia; it is the standard arterial system design in all placentals at least as large as rabbits, including humans. Formed initially as one-layer endothelium lining, this phenotype can either be maintained or differentiate into a normal multi-layer cellular lining, so striking in its resemblance to diseased hyperplasia that we have to name it "benign intimal hyperplasia". However, normal or "benign " intimal hyperplasia, although microscopically identical to pathology, is a controllable phenotype that rarely compromises blood supply. It is remarkable that each human heart has coronary arteries in which a single-layer endothelium differentiates earl

Comparative analysis of dendritic cell density and total number in commonly transplanted organs: morphometric estimation in normal mice

Dendritic cells (DC) are considered to be the major cell type responsible for induction of primary immune responses. While they have been shown to play a critical role in eliciting allosensitization via the direct pathway, there is evidence that maturational and/or activational heterogeneity between DC in different donor organs may be crucial to allograft outcome. Despite such an important perceived role for DC, no accurate estimates of their number in commonly transplanted organs have been reported. Therefore, leukocytes and DC were visualized and enumerated in cryostat sections of normal mouse (C57BL/10, B10.BR, C3H) liver, heart, kidney and pancreas by immunohistochemistry (CD45 and MHC class II staining, respectively). Total immunopositive cell number and MHC class II+ cell density (C57BL/10 mice only) were estimated using established morphometric techniques - the fractionator and disector principles, respectively. Liver contained considerably more leukocytes (similar to 5-20 x 10(6)) and DC (similar to 1-3 x 10(6)) than the other organs examined (pancreas: similar to 0.6 x 10(6) and similar to 0.35 x 10(6): heart: similar to 0.8 x 10(6) and similar to 0.4 x 10(6); kidney similar to 1.2 x 10(6) and 0.65 x 10(6), respectively). In liver, DC comprised a lower proportion of all leukocytes (similar to 15-25%) than in the other parenchymal organs examined (similar to 40-60%). Comparatively, DC density in C57BL/10 mice was heart > kidney > pancreas much greater than liver (similar to 6.6 x 10(6), 5 x 10(6), 4.5 x 10(6) and 1.1 x 10(6) cells/cm(3), respectively). When compared to previously published data on allograft survival, the results indicate that the absolute number of MHC class II+ DC present in a donor organ is a poor predictor of graft outcome. Survival of solid organ allografts is more closely related to the density of the donor DC network within the graft. (C) 2000 Elsevier Science B.V. All rights reserved

Rapid intravascular injection into limb skeletal muscle: a damage assessment study

We have recently developed a simple and highly efficient methodology for delivering plasmid DNA (pDNA) to skeletal muscle cells of mammalian limbs. The procedure involves the rapid intravascular injection of a large volume of saline (containing pDNA) into the vasculature of the distal limb. As a result of the robust delivery methodology involved, it is important to understand the effects of the injection procedure on the skeletal muscle tissue in the targeted limb. In previous studies, only modest and transient muscle damage was noted. In this study we quantitatively assessed the degree of muscle damage in rat limbs following intravascular injections using muscle histology (H&E staining), membrane integrity (Evans blue staining), and leukocyte infiltration (immunohistochemistry) assays. The rapid extravasation of fluid during the injection process resulted in edema of the muscle tissue of the targeted limb; however, the edema was transient and resolved within 24 h. Consistent with observations from previous studies, minimal levels of myofiber damage were detected. Immunohistochemical labeling indicated that increased numbers of neutrophils (CD43+) and macrophages (ED1+ and ED2+) were present in the muscle tissue interstitium shortly after injection but that elevations were relatively modest and resolved by 2 weeks postinjection

Flt-3 Ligand Increases Microchimerism But Can Prevent the Therapeutic Effect of Donor Bone Marrow in Transiently Immunosuppressed Cardiac Allograft Recipients

C3H (H2(k)) mice received 50 x 10(6) B10 (H2(b)) bone marrow (BM) cells either alone or with fit-3 ligand (FL) (10 mu g/day), tacrolimus (2 mg/kg/day), or both agents for 7 days, Donor MHC class II+ (IA(b+)) cells were quantitated in spleens by immunohistochemical analysis, and donor class II DNA detected in BM by PCR, Donor cells were rare in the BM alone and BM + FL groups, whereas there was a substantial increase in chimerism in the BM + tacrolimus group, Addition of FL to BM + tacrolimus led to a further eightfold increase in donor cells and enhanced donor DNA compared with the BM + tacrolimus group, This increase in donor cells was almost 500-fold compared with BM alone, C3H recipients of B10 heart allografts given perioperative B10 BM and tacrolimus (days 0-13) exhibited a markedly extended median graft survival time (MST, 42 days) compared with those given tacrolimus alone (MST, 22 days), Addition of FL (10 mu g/day; 7 days) to BM + tacrolimus prevented the beneficial effect of donor BM (MST, 18 days), BM alone or BM + FL resulted in uniform early heart graft failure (MST < 8 days), Functional studies revealed maximal antidonor MLR and CTL activities in the BM- and BM + FL-treated groups, with minimal activity in the tacrolimus-treated groups, Thus, dramatic growth factor-induced increases in chimerism achieved under cover of immunosuppression may result in augmented antidonor T cell reactivity and reduced graft survival after immunosuppressive drug withdrawal, With FL, this map reflect striking augmentation of immunostimulatory dendritic cells