Vascular Leak Syndrome

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Ribbon model of interleukin-2
Edema as a result of an interleukin- 11 induced VLS
Penile edema as a result of an interleukin- 11 induced VLS

The Vascular leak syndrome ( Engl. Vascular leak syndrome , VLS ) is a in the treatment with cytokines - particularly interleukin-2 - or immunotoxins based on interleukin-2 observed serious side effect .

description

The Vascular leak syndrome is a (engl. By an increase in the permeability of leak = leakage ',' leakage ') of the blood vessels (engl. Vascular =, vascular') conditional syndrome . The permeability of blood vessels has an extravasation ( extravasation ) of fluid and proteins into the interstitium results in causing an edema and ultimately to a lethal organ failure can result. Correspondingly, the affected patients - caused by the abnormal accumulation of body fluid - show an increase in body weight ("dropsy"), peripheral edema, pleural effusion , pericardial effusion ( pericardial effusion ), ascites ( ascites ) and anasarca . In severe cases, there are signs of heart and lung failure (ADRS). Depending on the patient, the symptoms can vary greatly with the same dose of the therapeutic agent (interleukin-2 or an immunotoxin). The vascular leak syndrome limits the dose during therapy with Interkleukin-2 and immunotoxins and can lead to discontinuation of the therapy. Statistically, about 3% of patients treated with interleukin-2 die as a result of the therapy.

The immunotoxin denileukin Diftitox , approved in the United States for the treatment of refractory cutaneous T-cell lymphomas , is an immunoconjugate consisting of interleukin-2 and the diphtheria toxin . Treatment with this drug has also resulted in deaths due to the vascular leak syndrome. Large immunotoxin molecules that circulate in the bloodstream for a long time favor the development of a vascular leak syndrome. Newer immunotoxins, which are still being developed, sometimes have a modified protein structure in order to circumvent the problem of the vascular leak syndrome.

For some potential drugs, the appearance of vascular leak syndrome in the early stages of clinical trials has resulted in the discontinuation of further trials.

root cause

The exact pathogenesis of the vascular leak syndrome is still largely unclear and obviously very complex. Damage to the endothelial cells of the blood vessels is a major factor in VLS caused by interleukin-2. The endothelial cells of the blood vessels can be damaged by the release of leukocytes , other cytokines and inflammatory messenger substances , as well as changes in the cell adhesion of the endothelia to one another or to the extracellular matrix . The apoptosis (programmed cell death) of the endothelium plays a role.

Therapy and approaches to avoid the VLS

So far there is no effective therapy for vascular leak syndrome. Various approaches to suppressing this undesirable side effect of interleukin-2 are being discussed and tested, as interleukin is a highly potent active ingredient which, by activating the immune system, has a high therapeutic potential against tumor diseases ( e.g. renal cell carcinoma and malignant melanoma ), other cancers such as leukemia and lymphoma , as well as against viral diseases such as AIDS .

Hyaluronic acid , an important component of connective tissue , appears to play an essential role in vascular leakage syndrome. In the animal model , blocking or gene knockout of CD44 , the main receptor of hyaluronic acid, significantly suppressed the vascular leak syndrome.

Another approach to avoiding vascular leak syndrome is to avoid certain motifs in the peptide sequence of interleukin-2, which apparently play an important role in the pathogenesis of the VLS. This motif is believed to be responsible for the binding of interleukin-2 to the endothelial cells.

In mice, administration of histamine increased the survival rate after administration of interleukin-2.

further reading

  • J. Li and ZK Zhang: LHRH-PE40-Induced Vascular Leak Syndrome. In: Toxicol Mech Methods 16, 2006, pp. 473-476. PMID 20021022
  • A. Assier et al .: Constitutive expression of IL-2Rbeta chain and its effects on IL-2-induced vascular leak syndrome. In: Cytokine 32, 2005, pp. 280-286. PMID 16378732
  • A. Assier et al: NK cells and polymorphonuclear neutrophils are both critical for IL-2-induced pulmonary vascular leak syndrome. In: J Immunol 172, 2004, pp. 7661-7668. PMID 15187148
  • AL Lindstrom and CA Pennell: In vitro studies of ricin A-chain-induced vascular leak syndrome. In: Methods Mol Biol 166, 2001, pp. 125-135. PMID 11217363 (Review)
  • ES Vitetta: Immunotoxins and Vascular Leak Syndrome. In: Cancer J 6, 2000, pp. 218-224. PMID 10874491
  • JU Bascon: Vascular leak syndrome: a troublesome side effect of immunotherapy. In: Immunopharmacology 39, 1998, pp. 255-257. PMID 9754911
  • LH Pai et al .: Treatment of advanced solid tumors with immunotoxin LMB-1: An antibody linked to pseudomonas extotoxin. In: Nature Medicine 2, 1996, pp. 350-353. PMID 8612238

Individual evidence

  1. ↑ a b R. Baluna and ES Vitetta: Vascular leak syndrome: a side effect of immunotherapy. In: Immunopharmacology 37, 1997, pp. 117-132. PMID 9403331
  2. ↑ Specialist information: Proleukin ( Memento of the original from June 24, 2007 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. December 1994 @1@ 2Template: Webachiv / IABot / www.dgfit.de
  3. ↑ AB Avarbock et al .: Lethal vascular leak syndrome after denileukin diftitox administration to a patient with cutaneous gamma / delta T-cell lymphoma and occult cirrhosis. In: Am J Hematol 83, 2008, pp. 593-595. PMID 18335564
  4. ↑ M. Posch: New Approaches to the Targeted Treatment of Solid Tumors. Antisense oligonucleotides and immunotoxins for tumor cell-specific apoptosis induction. Dissertation, Charité Medical Faculty, Humboldt University Berlin, 2002
  5. ↑ M. Mathew and RS Verma: Humanized immunotoxins: a new generation of immunotoxins for targeted cancer therapy. In: Cancer Sci 100, 2009, pp. 1359-1365. PMID 19459847
  6. ↑ L. Beckerbauer et al .: Differential effects of FR900482 and FK317 on apoptosis, IL-2 gene expression, and induction of vascular leak syndrome. In: Chem Biol 9, 2002, pp. 427-441. PMID 11983332
  7. ↑ a b c H. Guan et al .: Blockade of hyaluronan inhibits IL-2-induced vascular leak syndrome and maintains effectiveness of IL-2 treatment for metastatic melanoma. In: J Immunol 179, 2007, pp. 3715-3723. PMID 17785808
  8. ^ AQ Rafi et al: Evidence for the involvement of Fas ligand and perforin in the induction of vascular leak syndrome. In: J Immunol 161, 1998, pp. 3077-3086. PMID 9743374
  9. ↑ AB Lentsch et al .: Mechanisms of leukocyte-mediated tissue injury induced by interleukin-2. In: Cancer Immunol Immunother 47, 1999, pp. 243-248. PMID 10022467
  10. ↑ A. Mustafa et al: Regulation of interleukin-2-induced vascular leak syndrome by targeting CD44 using hyaluronic acid and anti-CD44 antibodies. In: Journal of Immunotherapy 25, 2002, pp. 476-488. PMID 12439345
  11. ↑ M. Posch: New Approaches to the Targeted Treatment of Solid Tumors. Antisense oligonucleotides and immunotoxins for tumor cell-specific apoptosis induction. Dissertation, Charité Medical Faculty, Humboldt University Berlin, 2002
  12. ↑ SA Rosenberg et al.: Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. In: J Am Med Assoc 271, 1994, pp. 907-913. PMID 8120958
  13. ↑ LM Chelstrom et al .: Treatment of BCL-1 murine B-cell leukemia with recombinant cytokines. Comparative analysis of the anti-leukemic potential of interleukin 1 beta (IL-1 beta), interleukin 2 (IL-2), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF alpha), granulocyte colony stimulating factor ( G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), and their combination .. In: Leukemia & Lymphoma 7, 1992, pp. 79-86. PMID 1282065
  14. ↑ I. Sereti et al .: Long-term effects of intermittent interleukin 2 therapy in patients with HIV infection: characterization of a novel subset of CD4 + / CD25 + T cells. In: Blood 100, 2002, pp. 2159-2167. PMID 12200381
  15. ^ V. Natarajan, RA Lempicki, I. Sereti, Y. Badralmaa, JW Adelsberger, JA Metcalf, DA Prieto, R. Stevens, MW Baseler, JA Kovacs, HC Lane: Increased peripheral expansion of naive CD4 + T cells in vivo after IL -2 treatment of patients with HIV infection. In: Proceedings of the National Academy of Sciences . Volume 99, number 16, August 2002, pp. 10712-10717, doi : 10.1073 / pnas.162352399 , PMID 12149467 , PMC 125022 (free full text).
  16. ↑ EL Jacobson et al.: Rational interleukin 2 therapy for HIV positive individuals: daily low doses enhance immune function without toxicity. In: PNAS 93, 1996, pp. 10405-10410. PMID 8816813
  17. ↑ R. Baluna, J. Rizo, BE Gordon, V. Ghetie, ES Vitetta: Evidence for a structural motif in toxin and interleukin-2 did may be responsible for binding to endothelial cells and initiating vascular leak syndrome. In: Proceedings of the National Academy of Sciences . Volume 96, Number 7, March 1999, pp. 3957-3962, PMID 10097145 , PMC 22402 (free full text).
  18. ^ H. Wang: Treatment of hepatocellular carcinoma in a mouse xenograft model with an immunotoxin which is engineered to eliminate vascular leak syndrome. In: Cancer Immunol Immunother 56, 2007, pp. 1775-1783. PMID 17431617
  19. ↑ SC Hornyak et al .: Histamine improves survival and protects against interleukin-2-induced pulmonary vascular leak syndrome in mice. In: Vascul Pharmacol 42, 2005, pp. 187-193. PMID 15820445

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