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1.  Long-term effects of Alemtuzumab on regulatory and memory T cell subsets in kidney transplantation 
Transplantation  2012;93(8):813-821.
Background
Induction with lymphocyte-depleting antibodies is routinely employed to prevent rejection but often skews T cells towards memory. It is not fully understood which memory and regulatory T cell subsets are most affected and how they relate to clinical outcomes.
Methods
We analyzed T cells from 57 living-donor renal transplant recipients (12 reactive and 45 quiescent) 2.8±1.4 years after Alemtuzumab induction. 34 healthy subjects and 9 patients with acute cellular rejection (ACR) were also studied.
Results
We found that Alemtuzumab caused protracted CD4>CD8 T lymphocyte deficiency, increased proportion of CD4+ memory T cells (TM), and decreased proportion of CD4+ regulatory T cells (TREG). Reactive patients exhibited higher proportions of CD4+ effector memory (TEM) and CD8+ terminally differentiated effector memory (TEMRA), with greater CD4+ TEM and CD8+ TEMRA to TREG ratios, than quiescent patients or healthy controls. Patients with ongoing ACR had profound reduction in circulating CD8+ TEMRA. Mixed lymphocyte assays showed significantly lower T cell proliferation to donor than third party antigens in the quiescent group, while reactive and ACR patients exhibited increased effector molecules in CD8+ T cells.
Conclusions
Our findings provide evidence that T cell skewing towards effector memory may be associated with anti-graft reactivity long after lymphodepletion. Further testing of TEM and TEMRA subsets as rejection predictors is warranted.
doi:10.1097/TP.0b013e318247a717
PMCID: PMC3323763  PMID: 22343334
kidney transplantation; memory T cells; regulatory T cells; alemtuzumab
2.  Prevention of Transplant Rejection 
Clinical immunotherapeutics  1996;6(2):89-96.
Summary
Successful solid organ transplantation is generally attributed to the increasingly precise ability of drugs to control rejection. However, it was recently shown that a few donor haematolymphoid cells can survive for decades in recipients of successful organ allografts, a phenomenon called microchimaerism. The association for decades of haematolymphoid chimaerism with allograft tolerance in experimental transplantation suggests that immunosuppressive drugs merely create a milieu that enables an allograft and its complement of passenger leucocytes to prime the recipient for graft acceptance.
Exploitation of this concept requires a fundamental shift in the classical view of passenger leucocytes only as initiators of rejection. Microchimaerism has taught us that solid organ transplantation involves the transfer of two donor organ systems to the recipient: the allograft parenchyma and the donor haematolymphoid system in the form of donor stem cells contained within the passenger leucocyte compartment. Each has the potential to integrate with the corresponding recipient system and carry out normal physiological functions, such as immunological self definition. Resistance to initial integration by mature T cells requires some form of immunosuppression, but maintenance of donor immune system function will depend on renewable supply of cells, which can be provided by engrafted progenitors. Successful clinical application will depend on the development of low morbidity methods to enhance engraftment of donor haemopoietic stem cells.
PMCID: PMC3091025  PMID: 21566684
3.  Digital Transplantation Pathology: Combining Whole Slide Imaging, Multiplex Staining, and Automated Image Analysis 
Conventional histopathology is the gold standard for allograft monitoring, but its value proposition is increasingly questioned. “-Omics” analysis of tissues, peripheral blood and fluids and targeted serologic studies provide mechanistic insights into allograft injury not currently provided by conventional histology. Microscopic biopsy analysis, however, provides valuable and unique information: a) spatial-temporal relationships; b) rare events/cells; c) complex structural context; and d) integration into a “systems” model. Nevertheless, except for immunostaining, no transformative advancements have “modernized” routine microscopy in over 100 years.
Pathologists now team with hardware and software engineers to exploit remarkable developments in digital imaging, nanoparticle multiplex staining, and computational image analysis software to bridge the traditional histology - global “–omic” analyses gap. Included are side-by-side comparisons, objective biopsy finding quantification, multiplexing, automated image analysis, and electronic data and resource sharing. Current utilization for teaching, quality assurance, conferencing, consultations, research and clinical trials is evolving toward implementation for low-volume, high-complexity clinical services like transplantation pathology. Cost, complexities of implementation, fluid/evolving standards, and unsettled medical/legal and regulatory issues remain as challenges. Regardless, challenges will be overcome and these technologies will enable transplant pathologists to increase information extraction from tissue specimens and contribute to cross-platform biomarker discovery for improved outcomes.
doi:10.1111/j.1600-6143.2011.03797.x
PMCID: PMC3627485  PMID: 22053785
Digital image; Fibrosis; Quantitative analysis; Allograft pathology; C4d; 3-dimensional imaging; Quantum dots
4.  Profound depletion of host conventional dendritic cells, plasmacytoid dendritic cells and B cells does not prevent GVHD induction 
The efficacy of alloSCT is limited by graft-versus-host disease (GVHD). Host hematopoietic antigen presenting cells (APCs) are important initiators of GVHD making them logical targets for GVHD prevention. Conventional dendritic cells (cDCs) are key APCs for T cell responses in other models of T cell immunity and they are sufficient for GVHD induction. However, we report here in two polyclonal GVHD models in which host hematopoietic APCs are essential, that GVHD was not decreased when recipient cDCs were inducibly or constitutively deleted. Additional profound depletion of plasmacytoid DCs and B cells, with or without partial depletion of CD11b+ cells, also did not ameliorate GVHD. These data indicate that, in contrast to pathogen models, there is a surprising redundancy as to which host cells can initiate GVHD. Alternatively, very low numbers of targeted APCs were sufficient. We hypothesize the difference in APC requirements in pathogen and GVHD models relates to the availability of target antigens. In anti-pathogen responses specialized APCs are uniquely equipped to acquire and present exogenous antigens whereas in GVHD all host cells directly present alloantigens. These studies make it unlikely that reagent-based host APC depletion will prevent GVHD in the clinic.
doi:10.4049/jimmunol.1102795
PMCID: PMC3324629  PMID: 22422880
5.  Innate immunity alone is not sufficient for chronic rejection but predisposes healed allografts to T cell-mediated pathology1 
Transplant Immunology  2011;26(2-3):113-118.
Background
Acute allograft rejection is dependent on adaptive immunity, but it is unclear whether the same is true for chronic rejection. Here we asked whether innate immunity alone is sufficient for causing chronic rejection of mouse cardiac allografts.
Methods
We transplanted primarily vascularized cardiac grafts to recombinase activating gene-knockout (RAG−/−) mice that lack T and B cells but have an intact innate immune system. Recipients were left unmanipulated, received adjuvants that stimulate innate immunity, or were reconstituted with B-1 lymphocytes to generate natural IgM antibodies. In a second model, we transplanted cardiac allografts to mice that lack secondary lymphoid tissues (splenectomized aly/aly recipients) and studied the effect of NK cell inactivation on T cell-mediated chronic rejection.
Results
Acute cardiac allograft rejection was not observed in any of the recipients. Histological analysis of allografts harvested 50 to 90 days after transplantation to RAG−/− mice failed to identify chronic vascular or parenchymal changes beyond those observed in control syngeneic grafts. Chronic rejection of cardiac allografts parked in splenectomized aly/aly mice was observed only after the transfer of exogenously activated T cells. NK inactivation throughout the experiment, or during the parking period alone, reduced the severity of T cell- dependent chronic rejection.
Conclusions
The innate immune system alone is not sufficient for causing chronic rejection. NK cells predispose healed allografts to T cell-dependent chronic rejection and may contribute to chronic allograft pathology.
doi:10.1016/j.trim.2011.12.006
PMCID: PMC3277291  PMID: 22226941
innate immunity; chronic rejection; NK cells; B-1 lymphocytes
6.  Enhancing alloreactivity does not restore GVHD induction but augments skin graft rejection by CD4 effector memory T cells 
European journal of immunology  2011;41(9):2782-2792.
Graft-vs.-host disease (GVHD) caused by donor T cells attacking recipient tissues is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (alloSCT). Studies have shown that effector memory T cells (TEM) do not cause GVHD but are capable of immune functions post-transplant, including graft-vs.-leukemia (GVL) effects, but the reasons for this are unclear. In mice, the TEM pool may have a less-diverse T cell receptor (TCR) repertoire than TN with fewer alloreactive clones. We therefore tested whether enhancing the alloreactivity of TEM would restore their ability to cause GVHD. In an MHC-matched system, alloreactive TEM were created by transferring GVHD effector cells into syngeneic recipients and allowing conversion to TEM. Upon retransfer to freshly transplanted recipients, these cells caused only mild GVHD. Similarly, in an MHC-mismatched system, TEM with a proven increased precursor frequency of alloreactive clones only caused limited GVHD. Nonetheless these same cells mounted strong in vitro alloresponses and caused rapid skin graft rejection. TEM created from CD4 cells that had undergone lymphopenia-induced proliferation also caused only mild GVHD. Our findings establish that conversion to TEM significantly reduces GVHD potency, even in cells with a substantially enhanced alloreactive repertoire.
doi:10.1002/eji.201141678
PMCID: PMC3517133  PMID: 21660940
7.  Pre-existing Epithelial Diversity in Normal Human Livers: A Tissue-tethered Cytometric Analysis in Portal/Periportal Epithelial Cells 
Hepatology (Baltimore, Md.)  2013;57(4):1632-1643.
Routine light microscopy identifies two distinct epithelial cell populations in normal human livers: hepatocytes and biliary epithelial cells (BEC). Considerable epithelial diversity, however, arises during disease states when a variety of hepatocyte-BEC hybrid cells appear. This has been attributed to activation and differentiation of putative hepatic progenitor cells (HPC) residing in the Canals of Hering and/or metaplasia of pre-existing mature epithelial cells. A novel analytic approach consisting of multiplex labeling, high resolution whole slide imaging (WSI), and automated image analysis was used to determine if more complex epithelial cell phenotypes pre-existed in normal adult human livers, which might provide an alternative explanation for disease-induced epithelial diversity. “Virtually digested” WSI enabled quantitative cytometric analyses of individual cells displayed in a variety of formats (e.g. scatter plots) while still tethered to the WSI and tissue structure. We employed biomarkers specifically-associated with mature epithelial forms (HNF4α for hepatocytes, CK19 and HNF1β for BEC) and explored for the presence of cells with hybrid biomarker phenotypes. Results showed abundant hybrid cells in portal bile duct BEC, canals of Hering, and immediate periportal hepatocytes. These bi-potential cells likely serve as a reservoir for the epithelial diversity of ductular reactions, appearance of hepatocytes in bile ducts, and the rapid and fluid transition of BEC to hepatocytes, and vice versa.
Conclusion
Novel imaging and computational tools enable increased information extraction from tissue samples and quantify the considerable pre-existent hybrid epithelial diversity in normal human liver. This computationally-enabled tissue analysis approach offers much broader potential beyond the results presented here.
doi:10.1002/hep.26131
PMCID: PMC3612393  PMID: 23150208
Digital imaging; progenitor cells; Canals of Hering; hepatocyte nuclear factors; fluorescence microscopy
8.  SPRR2A enhances p53 deacetylation through HDAC1 and down regulates p21 promoter activity 
BMC Molecular Biology  2012;13:20.
Background
Small proline rich protein (SPRR) 2A is one of 14 SPRR genes that encodes for a skin cross-linking protein, which confers structural integrity to the cornified keratinocyte cell envelope. New evidence, however, shows that SPRR2A is also a critical stress and wound repair modulator: it enables a variety of barrier epithelia to transiently acquire mesenchymal characteristics (EMT) and simultaneously quench reactive oxygen species during wound repair responses. p53 is also widely recognized as the node in cellular stress responses that inhibits EMT and triggers cell-cycle arrest, apoptosis, and cellular senescence. Since some p53-directed processes would seem to impede wound repair of barrier epithelia, we hypothesized that SPRR2A up regulation might counteract these effects and enable/promote wound repair under stressful environmental conditions.
Results
Using a well characterized cholangiocarcinoma cell line we show that levels of SPRR2A expression, similar to that seen during stressful biliary wound repair responses, disrupts acetylation and subsequent p53 transcriptional activity. p53 deacetylation is accomplished via two distinct, but possibly related, mechanisms: 1) a reduction of p300 acetylation, thereby interfering with p300-p53 binding and subsequent p300 acetylation of K382 in p53; and 2) an increase in histone deacetylase 1 (HDAC1) mRNA and protein expression. The p300 CH3 domain is essential for both the autoacetylation of p300 and transference of the acetyl group to p53 and HDAC1 is a component of several non-p300 complexes that enhance p53 deacetylation, ubiquitination, and proteosomal degradation. HDAC1 can also bind the p300-CH3 domain, regulating p300 acetylation and interfering with p300 mediated p53 acetylation. The importance of this pathway is illustrated by showing complete restoration of p53 acetylation and partial restoration of p300 acetylation by treating SPRR2A expressing cells with HDAC1 siRNA.
Conclusion
Up-regulation of SPRR2A, similar to that seen during barrier epithelia wound repair responses reduces p53 acetylation by interfering with p300-p53 interactions and by increasing HDAC1 expression. SPRR2A, therefore, functions as a suppressor of p53-dependent transcriptional activity, which otherwise might impede cellular processes needed for epithelial wound repair responses such as EMT.
doi:10.1186/1471-2199-13-20
PMCID: PMC3495018  PMID: 22731250
9.  Memory T cells migrate to and reject vascularized cardiac allografts independent of the chemokine receptor CXCR31 
Transplantation  2011;91(8):827-832.
Background
Memory T cells migrate to and reject transplanted organs without the need for priming in secondary lymphoid tissues, but the mechanisms by which they do so are not known. Here we tested whether CXCR3, implicated in the homing of effector T cells to sites of infection, is critical for memory T cell migration to vascularized allografts.
Methods
CD4 and CD8 memory T cells were sorted from alloimmunized CXCR3−/− and wildtype B6 mice and co-transferred to congenic B6 recipients of BALB/c heart allografts. Graft-infiltrating T cells were quantitated 20 and 72 hours later by flow cytometry. Migration and allograft survival were also studied in splenectomized alymphoplastic (aly/aly) recipients, which lack secondary lymphoid tissues.
Results
We found that polyclonal and antigen-specific memory T cells express high levels of CXCR3. No difference in migration of wildtype vs CXCR3−/− CD4 and CD8 memory T cells to allografts could be detected in either wildtype or aly/aly hosts. In the latter, wildtype and CXCR3−/−memory T cells precipitated acute rejection at similar rates. Blocking CCR5, a chemokine receptor also upregulated on memory T cells, did not delay graft rejection mediated by CXCR3−/− memory T cells.
Conclusions
CXCR3 is not critical for the migration of memory T cells to vascularized organ allografts. Blocking either CXCR3 or CXCR3 and CCR5 does not delay acute rejection mediated by memory T cells. These findings suggest that the mechanisms of memory T cell homing to transplanted organs may be distinct from those required for their migration to sites of infection.
doi:10.1097/TP.0b013e31820f0856
PMCID: PMC3073028  PMID: 21285915
T lymphocyte; chemokine receptor; transplantation; rejection
11.  SPLIT TOLERANCE INDUCED BY ORTHOTOPIC LIVER TRANSPLANTATION IN MICE1 
Transplantation  1994;58(1):1-8.
Spontaneous orthotopic liver allograft acceptance associated with microchimerism in mice induces tolerance to subsequent skin or heart transplants from the donor but not third-party animals. Despite in vivo hyporesponsiveness, in vitro MLC and CTL assays showed continuing antidonor reactivity. Cells isolated from recipients’ spleens and grafted livers, when tested in MLC and CTL assays, were antidonor reactive out to 3 months to the same degree as splenocytes obtained from either naive or presensitized (with skin or heart) mice. Nevertheless, passive transfer of splenocytes or liver lymphocytes from liver tolerant mice, but not naive or sensitized donor strain mice, were able to prolong skin graft survival significantly in naive irradiated recipients. By using a strain combination in which the donor but not the recipient expressed the stimulatory endogenous super-Ag (Mlsf), it was possible to determine whether super-Ag-reactive T cells bearing Vβ5 and Vβ11 were deleted or anergic. Phenotypic analysis of cells isolated from recipients’ spleens and grafted livers (up to 90 days after transplant), when compared with naive animals, showed no significant difference in Vβ5 and Vβ11 TCR expression. Additionally, when these isolated spleen cells were tested for antibody-mediated stimulation, both anti-Vβ5 and Vβ11 TCR mAb led to marked proliferation of cells obtained from naive and liver-transplanted recipients, but as expected, proliferation was very low in cells from naive donors. These results suggest that liver transplantation induces donor-specific tolerance in vivo, which may not be reflected in in vitro proliferative and cytotoxicity assays (split tolerance). Furthermore, this tolerance does not seem to be induced by clonal deletion or anergy of minor-lymphocyte-stimulating-antigen-reactive T cells in the recipients.
PMCID: PMC3208349  PMID: 8036695
12.  DONOR HEMATOPOIETIC PROGENITOR CELLS IN NONMYELOABLATED RAT RECIPIENTS OF ALLOGENEIC BONE MARROW AND LIVER GRAFTS1 
Transplantation  1999;67(6):833-840.
Background
Although the persistence of multilineage microchimerism in recipients of long-surviving organ transplants implies engraftment of migratory pluripotent donor stem cells, the ultimate localization in the recipient of these cells has not been determined in any species.
Methods
Progenitor cells were demonstrated in the bone marrow and nonparenchymal liver cells of naive rats and in Brown Norway (BN) recipients of Lewis (LEW) allografts by semiquantitative colony-forming unit in culture (CFU-C) assays. The LEW allografts of bone marrow cells (BMC) (2.5×108), orthotopic livers, or heterotopic hearts (abdominal site) were transplanted under a 2-week course of daily tacrolimus, with additional single doses on days 20 and 27. Donor CFU-C colonies were distinguished from recipient colonies in the allografts and recipient bone marrow with a donor-specific MHC class II monoclonal antibody. The proportions of donor and recipient colonies were estimated from a standard curve created by LEW and BN bone marrow mixtures of known concentrations.
Results
After the BMC infusions, 5–10% of the CFU-C in the bone marrow of BN recipients were of the LEW phenotype at 14, 30, and 60 days after transplantation. At 100 days, however, donor CFU-C could no longer be found at this site. The pattern of LEW CFU-C in the bone marrow of BN liver recipients up to 60 days was similar to that in recipients of 2.5 × 108 BMC, although the donor colonies were only 1/20 to 1/200 as numerous. This was expected, because the progenitor cells in the passenger leukocytes of a single liver are equivalent to those in 1–5×106 BMC. Using a liquid CFU-C assay, donor progenitor cells were demonstrated among the nonparenchymal cells of liver allografts up to 100 days. In contrast, after heart transplantation, donor CFU-C could not be identified in the recipient bone marrow, even at 14 days.
Conclusion
Under effective immunosuppression, allogeneic hematopoietic progenitors compete effectively with host cells for initial engraftment in the bone marrow of noncytoablated recipients, but disappear from this location between 60 and 100 days after transplantation, coincident with the shift of donor leukocyte chimerism from the lymphoid to the nonlymphoid compartment that we previously have observed in this model. It is possible that the syngeneic parenchymal environment of the liver allografts constitutes a privileged site for persistent progenitor donor cells.
PMCID: PMC3184835  PMID: 10199731
14.  Recipient B Cells Are Not Required For GVHD Induction 
Recipient antigen presenting cells (APCs) are required for CD8-mediated GVHD and have an important and nonredundant role in CD4-mediated GVHD in mouse MHC-matched allogeneic bone marrow transplantation (alloBMT). However, the precise roles of specific recipient APCs — dendritic cells, macrophages, and B cells — are not well defined. If recipient B cells are important APCs they could be depleted with Rituximab, an anti-CD20 monoclonal antibody. On the other hand, B cells can downregulate T cell responses and consequently B cell depletion could exacerbate GVHD. Patients with B cell lymphomas undergo allogeneic hematopoietic stem cell transplantation (alloSCT) and many are B-cell-deficient due to prior Rituximab. We therefore studied the role of recipient B cells in MHC-matched murine models of CD8- and CD4-mediated GVHD by using recipients genetically deficient in B cells and with antibody-mediated depletion of host B cells. In both CD4-and CD8-dependent models, B cell deficient recipients developed clinical and pathologic GVHD. However, although CD8-mediated GVHD was clinically less severe in hosts genetically deficient in B cells, it was unaffected in anti-CD20-treated recipients. These data indicate that recipient B cells are not important initiators of GVHD and that efforts to prevent GVHD by APC depletion should focus on other APC subsets.
doi:10.1016/j.bbmt.2010.03.015
PMCID: PMC3135976  PMID: 20338255
15.  Production of α1,3-Galactosyltransferase–Deficient Pigs 
Science (New York, N.Y.)  2002;299(5605):411-414.
The enzyme α1,3-galactosyltransferase (α1,3GT or GCTA1) synthesizes α1,3-galactose (α1,3Gal) epitopes (Galα1,3Galβ1,4GlcNAc-R), which are the major xenoantigens causing hyperacute rejection in pig-to-human xenotransplantation. Complete removal of α1,3Gal from pig organs is the critical step toward the success of xenotransplantation. We reported earlier the targeted disruption of one allele of the α1,3GT gene in cloned pigs. A selection procedure based on a bacterial toxin was used to select for cells in which the second allele of the gene was knocked out. Sequencing analysis demonstrated that knockout of the second allele of the α1,3GT gene was caused by a T-to-G single point mutation at the second base of exon 9, which resulted in inactivation of the α1,3GT protein. Four healthy α1,3GT double-knockout female piglets were produced by three consecutive rounds of cloning. The piglets carrying a point mutation in the α1,3GT gene hold significant value, as they would allow production of α1,3Gal-deficient pigs free of antibiotic-resistance genes and thus have the potential to make a safer product for human use.
doi:10.1126/science.1078942
PMCID: PMC3154759  PMID: 12493821
17.  Early Passenger Leukocyte Migration and Acute Immune Reactions in the Rat Recipient Spleen During Liver Engraftment: With Particular Emphasis on Donor Major Histocompatibility Complex Class II+ Cells1 
Transplantation  2002;74(1):103-111.
After a short course of tacrolimus, Lewis rat liver allografts induce donor-specific nonreactivity in Brown Norway recipients that is immunosuppression-independent after 28 days. To clarify the role of donor major histocompatibility complex (MHC) class II+ cells, we investigated the migration to the recipient splenic T- and B-cell compartments of different subsets of Lewis MHC class II+ passenger leukocytes. The rise and decline of immune activation were monitored in the hepatic allograft and in the host spleen by analyses of BrdU+ (proliferating) leukocytes, TUNEL+ (apoptotic) cells, apoptosis-associated molecules, TH1/ TH2 cytokine profiles, and histoimmunocytochemical examination of graft and splenic tissues. Serial flow cytometry studies during the 28-day period of drug-assisted “hepatic tolerogenesis” showed that migratory MHC class II+ cells accounted for less than half of the donor cells in the host spleen. The class II+ cells consisted mostly of B cells that homed to splenic B-cell follicles with only a sparse representation of dendritic cells that were exclusively found in the splenic periarteriolar lymphoid sheath. In parallel studies, transplantation of the less tolerogenic heart produced a diminutive version of the same events, but with far fewer donor cells in the host spleen, evidence of sustained immune activation, and the development of chronic rejection by 100 days. The data are consistent with the paradigm that migration of donor leukocytes is the prime determinant of variable tolerance induction induced by transplantation of the liver and other organs, but without regard for donor MHC class II+ expression.
PMCID: PMC3154775  PMID: 12134107
18.  Donor Species Complement After Liver Xenotransplantation 
Transplantation  1994;57(6):918-922.
Hamster hearts transplanted into stable rat recipients of hamster livers (OLT rats) were hyperacutely rejected after transfer with unaltered rat antihamster hyperimmune serum (HS). This was followed by immediate liver xenograft rejection in 4 of 5 rats. In contrast, simple heat inactivation of the rat HS resulted in prolonged survival of hamster hearts to 25 days without deterioration effect in the liver xenografts. This effect was species-specific because third-party mouse heart grafts in OLT rats were hyperacutely rejected in minutes if either active or heat inactivated antimouse HS was given. In cytotoxicity experiments, the complement in OLT serum produced weak lysis of hamster lymphocytes, while efficiently doing so with mouse cell targets. Because normal hamster serum caused no lysis at all of hamster target cells, the residual low-grade lysis of OLT serum was possibly being mediated by extrahepatic sources of rat C. In conclusion, the homology of C and target cells represents a mechanism of protection that the liver confers to other organs, and that is most easily seen in xenografts but may be allospecifically operational with allografts as well within the limits of MHC restriction.
PMCID: PMC3154791  PMID: 8154040
19.  Cytosolic Phospholipase A2α and PPAR-γ Signaling Pathway Counteracts TGF-β-mediated Inhibition of Primary and Transformed Hepatocyte Growth 
Hepatology (Baltimore, Md.)  2010;52(2):644-655.
Hepatocellular carcinoma often develops in the setting of abnormal hepatocyte growth associated with chronic hepatitis and liver cirrhosis. Transforming growth factor-βs (TGF-βs) are multifunctional cytokines pivotal in the regulation of hepatic cell growth, differentiation, migration, extracellular matrix production, stem cell homeostasis and hepatocarcinogenesis. However, the mechanisms by which TGF-βs influence hepatic cell functions remain incompletely defined. We report herein that TGF-β regulates the growth of primary and transformed hepatocytes through concurrent activation of Smad and phosphorylation of cPLA2α, a rate-limiting key enzyme that releases arachidonic acid for production of bioactive eicosanoids. The interplays between TGF-β and cPLA2α signaling pathways were examined in rat primary hepatocytes, human hepatocellular carcinoma cells and hepatocytes isolated from the newly developed cPLA2α transgenic mice. Our data show that cPLA2α activates PPAR-γ and thus counteracts Smad2/3-mediated inhibition of cell growth. Therefore, regulation of TGF-β signaling by cPLA2α and PPAR-γ may represent an important mechanism for control of hepatic cell growth and hepatocarcinogenesis.
doi:10.1002/hep.23703
PMCID: PMC3013516  PMID: 20683962
Transforming growth factor-β; cytosolic phospholipase A2α; peroxisome proliferator activated receptor-γ; hepatocyte; liver
21.  Transplantation for Primary Biliary Cirrhosis 
Gastroenterology  1988;94(5 Pt 1):1207-1216.
Primary biliary cirrhosis is a frequent indication for liver transplantation. The purpose of this report is to present our experience with liver transplantation for primary biliary cirrhosis. Attention is given to the causes of hepatic dysfunction seen in allografts. In addition, we review the postoperative problems encountered and the quality of life at time of last follow-up in patients with transplants for primary biliary cirrhosis. A total of 97 orthotopic liver transplant procedures were performed in 76 patients with advanced primary biliary cirrhosis at the University of Pittsburgh from March 1980 through September 1985. The transplant operation was relatively easy to perform. The most common technical complications experienced were fragmentation and intramural dissection of the recipient hepatic artery, which required an arterial graft in 20% of the cases. Most of the postoperative mortality occurred in the first 6 mo after transplantation, with an essentially flat actuarial life survival curve from that time point to a projected 5-yr survival of 66%. Common causes of death included rejection and primary graft nonfunction. Thirteen of the 76 patients had some hepatic dysfunction at the time of the last follow-up, although none were jaundiced. Recurrence of primary biliary cirrhosis could not be demonstrated in any of the patients. Antimitochondrial antibody was detected in the serum of almost all of the patients studied postoperatively for it. Most important, almost all of the 52 surviving patients have been rehabilitated socially and vocationally.
PMCID: PMC3095835  PMID: 3280389
24.  Medical Progress 
The New England journal of medicine  1989;321(15):1014-1022.
Advances in the management of both chronic and acute hepatic disease have been made possible and even mandated by the development of liver transplantation. The clinical use of transplantation has proceeded at a rapid pace since a Consensus Development Conference of the National Institutes of Health concluded in June 1983 that liver transplantation had become a service and not simply an experimental procedure.1
The liver can be transplanted as an extra (auxiliary) organ at an ectopic site, or in the orthotopic location after the removal of the host liver (Fig. 1). This article will focus primarily on the orthotopic procedure. However, there has been renewed interest in the auxiliary operation, which will be discussed separately.
doi:10.1056/NEJM198910123211505
PMCID: PMC3091023  PMID: 2674716
25.  THE INFLUENCE OF HLA MATCHING ON CYTOMEGALOVIRUS HEPATITIS AND CHRONIC REJECTION AFTER LIVER TRANSPLANTATION12 
Transplantation  1993;55(5):1067-1071.
Previous findings in liver transplantation patients have raised the concept that HLA plays a dualistic role. HLA matching will reduce rejection but may augment MHC restricted cellular immune mechanisms of liver allograft injury. To evaluate this concept, we studied CMV hepatitis in 399 FK506-treated liver transplant patients, including 355 cases for which complete HLA-A,B,DR,DQ typing information was available. CMV hepatitis developed in 25 patients, and 17 of them (or 68%) showed a one or two HLA-DR antigen match with the donor. In contrast, HLA-DR matches were found in only 35% of 330 patients without CMV hepatitis (P=0.005). No significant associations were seen for HLA-A, HLA-B, and HLA-DQ antigens. In pretransplant CMV-seronegative patients with seropositive grafts (n=39), the frequency of CMV hepatitis was 44% for HLA-DR-matched livers but 14% for HLA-DR-unmatched livers. In seropositive recipients (n=187), these frequencies were 12% and 2% for HLA-DR-matched and unmatched liver grafts. Chronic rejection developed in 29 patients (or 8%) during a follow-up between 10 and 24 months after transplantation. Its incidence was higher in the CMV hepatitis group (24% vs. 6%) (P=0.007). Although no associations were found between HLA matching and the incidence of chronic rejection, there was an earlier onset of chronic rejection of HLA-DR-matched livers irrespective of CMV hepatitis.
These findings suggest that an HLA-DR match between donor and recipient increases the incidence of CMV hepatitis in both primary and secondary CMV infections. Although HLA compatibility leads to less acute cellular rejection, it is suggested that DR matching may accelerate chronic rejection of liver transplants, perhaps through HLA-DR-restricted immunological mechanisms toward viral antigens, including CMV.
PMCID: PMC3091368  PMID: 8388584

Results 1-25 (125)