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Hauke Lang,Janine Baumgart,Jens Mittler 거트앤리버 소화기연관학회협의회 2020 Gut and Liver Vol.14 No.6
In 2007, the first associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure was performed in Regensburg, Germany. ALPPS is a variation of twostage hepatectomy to induce rapid liver hypertrophy allowing the removal of large tumors otherwise considered irresectable due to a too small future liver remnant. In 2012, the international ALPPS registry was created, and it now contains more than 1,000 cases. During the past years, improved patient selection and refinements in operative techniques, in particular, less invasive approaches such as Partial ALPPS, Tourniquet ALPPS, Ablation-assisted ALPPS, Hybrid ALPPS or Laparoscopic or Robotic approaches, have resulted in significant improvements in safety. The most frequent indication for ALPPS is colorectal liver metastases. In the first randomized controlled study, ALPPS provided a higher resectability rate than conventional two-stage hepatectomy, with similar complication rates. Long-term outcome data are still missing. The initial results of ALPPS for hepatocellular carcinoma and for perihilar cholangiocarcinoma were devastating, but with progress in surgical technic and better patient selection, ALPPS could serve as a treatment alternative in carefully selected cases, even for these tumors. ALPPS has enlarged the armamentarium of hepato-pancreato-biliary surgeons, but there is still discussion regarding how to use this novel technique, which may allow resection of tumors that are otherwise deemed irresectable.
Lee, Seung-Woo,Park, Yunji,So, Takanori,Kwon, Byoung S,Cheroutre, Hilde,Mittler, Robert S,Croft, Michael Nature Publishing Group 2008 Nature immunology Vol.9 No.8
The costimulatory molecule 4-1BB and its ligand 4-1BBL can control adaptive immunity, but here we show that their interaction also suppressed myelopoiesis. We found that 4-1BBL was expressed on hematopoietic stem cells, differentiating common myeloid progenitors and granulocyte-macrophage progenitors, and 4-1BB was inducible on activated myeloid progenitors. Steady-state numbers of granulocyte-macrophage progenitors, myeloid-lineage cells and mature dendritic cells were higher in 4-1BB- and 4-1BBL-deficient mice, indicative of a negative function, and we confirmed that result with bone marrow chimeras and in vitro, where the absence of interactions between 4-1BB and 4-1BBL led to enhanced differentiation into dendritic cell lineages. The regulatory activity was mediated by 4-1BBL, with binding by 4-1BB inhibiting differentiation of myeloid progenitors. Thus, 4-1BB and 4-1BBL have a previously unknown function in limiting myelopoiesis and the development of dendritic cells.
Mechanisms involved in synergistic anticancer effects of anti-4-1BB and cyclophosphamide therapy.
Kim, Young H,Choi, Beom K,Oh, Ho S,Kang, Woo J,Mittler, Robert S,Kwon, Byoung S American Association for Cancer Research, Inc 2009 Molecular Cancer Therapeutics Vol.8 No.2
<P>Chemotherapy can precondition for immunotherapy by creating an environment for homeostatic lymphoproliferation and eliminating some of the suppressive immune networks. We found that combination therapy with anti-4-1BB and cyclophosphamide (CTX) produced synergistic anticancer effects in the poorly immunogenic B16 melanoma model in mice. The antitumor effect of the combination therapy depended mainly on CD8(+) T cells, the 4-1BB-dependent expansion and differentiation of which into IFN-gamma-producing CD11c(+)CD8(+) T cells was enhanced by CTX. Anti-4-1BB induced a rapid repopulation of T and B cells from CTX-mediated lymphopenia. Anti-4-1BB protected naïve T cells from CTX and promoted proliferation of memory/effector and memory T cells. The combination treatment produced approximately 60- and 2.2-fold more CTLs per tumor-associated antigen compared with CTX or anti-4-1BB alone, respectively. This indicates that anti-4-1BB promoted a preferential expansion of tumor-specific CD8(+) T cells among the repopulated lymphocytes following CTX-mediated lymphopenia. CTX treatment enhanced 4-1BB expression on CD4 and CD8 T cells, and CTX alone or in combination with anti-4-1BB effectively suppressed peripheral regulatory T cells. Our results indicate that anti-4-1BB and CTX can be practical partners in cancer therapy because CTX creates an environment in which anti-4-1BB actively promotes the differentiation and expansion of tumor-specific CTLs.</P>
Myers, Lara,Lee, Seung Woo,Rossi, Robert J.,Lefrancois, Leo,Kwon, Byoung S.,Mittler, Robert S.,Croft, Michael,Vella, Anthony T. Oxford University Press 2006 International immunology Vol.18 No.2
<P>In practice, vaccines should induce lasting and efficacious T cell immunity without promoting deleterious pathological consequences. To accomplish this goal we immunized mice with ovalbumin peptide, polyinosinic–polycytidylic and anti-CD137. Vaccinated mice retained a massive functional CD8 T cell memory pool in lymphoid and non-lymphoid tissues for >1 year. The memory T cells clonally expanded, produced substantial amounts of IFNγ, and responded vigorously to vesicular stomatitis virus infection. To understand how the vaccine might function, we showed that the antigen-specific T cells must bear CD137 in order for optimal priming to occur. Thus, anti-CD137 agonist mAb directly stimulated peptide-specific CD8 T cells and conditioned them to survive. In contrast, CD137-deficient CD8 T cells did not survive despite CD137 expression by antigen presenting cells. Taken together, the data indicate that CD137 and adjuvant combined therapy is an efficacious vaccine strategy for immunization with non-replicating inert antigen.</P>
Kim, Hye J.,Lee, Jong S.,Kim, Ahra,Koo, Sumi,Cha, Hee J.,Han, Jae-A,Do, Yoonkyung,Kim, Kyung M.,Kwon, Byoung S.,Mittler, Robert S.,Cho, Hong R.,Kwon, Byungsuk The American Association of Immunologists, Inc. 2013 JOURNAL OF IMMUNOLOGY Vol.191 No.5
<P>Damage-associated molecular patterns released from damaged kidney cells initiate postischemic inflammation, an essential step in the progression of kidney ischemia–reperfusion injury (IRI). However, the mechanism that coordinates this highly specific process in ischemic kidneys remains to be clarified. Previously, we demonstrated that CD137 from NK cells specifically stimulates CD137 ligand (CD137L) on tubular epithelial cells (TECs) such that TECs produced the high CXCR2 chemokine levels required for neutrophil chemotaxis. We report in the present study that endogenous TLR2 ligands released from ischemic TECs induce CCR5 chemokine expression, which is critical to promoting NK cell recruitment. By implanting CD137L<SUP>−/−</SUP> TECs into the kidney capsule of TLR2<SUP>−/−</SUP> mice, we further showed that TLR2-mediated NK cell recruitment is an uncoupled event that can occur independently of CD137L signaling in TECs, which is responsible for recruiting neutrophils. Therefore, our findings identify TECs as both a target for kidney damage and also as a master regulator that actively modulates stepwise signaling, leading to the initiation and amplification of acute sterile inflammation that inflicts kidney IRI. Being clinically important, the signaling pathway of innate receptors in epithelial cells may therefore be a good target to block acute sterile inflammation resulting from tissue damage, including kidney IRI.</P>