Recombinant Human TNFRSF1A (r-hTBP1) Inhibits the Development of Endometriosis in Baboons: A Prospective, Randomized, Placebo- and Drug-Controlled Study1

Abstract

Endometriosis is associated with chronic inflammation, including an increased macrophage activity with increased secretion of cytokines, such as tumor necrosis factor (TNF) or TNF superfamily member 2, previously known as TNFalpha. In the present study, we tested the hypothesis that recombinant human TNFRSF1A (r-hTBP1) can inhibit the development of endometriotic lesions in the baboon, an established model for the study of endometriosis. Endometriosis was induced using intrapelvic injection of menstrual endometrium in 20 baboons with a normal pelvis. In the first part of the study, 14 baboons were randomly assigned to subcutaneous treatment with r-hTBP1, placebo, or GnRH antagonist (positive control). In the second part of the study, menstrual endometrium from 6 baboons was randomly incubated with either PBS or r-hTBP1 before intrapelvic seeding. Video laparoscopy was performed 25 days later to document the number, surface area, and estimated volume of endometriotic lesions and adhesions; to calculate the revised American Fertility Society (rAFS) score and stage; and to confirm the histological presence of endometriosis. In the first part, baboons treated with r-hTBP1 or with Antide (Bachem) had a lower endometriosis rAFS score, a lower surface area and estimated volume of peritoneal endometriotic lesions, and a lower histological confirmation rate compared with controls. Because of less adnexal and cul-de-sac adhesions, the number of baboons with endometriosis of stage II, III, or IV was lower among baboons treated with r-hTBP1 or Antide than among controls. In the second part, the surface area of endometriotic lesions was lower, and less severe endometriosis was observed in r-hTBP1-treated baboons. No hypoestrogenic effects were observed in baboons treated with r-hTBP1. In conclusion, r-hTBP1 can effectively inhibit the development of endometriosis without hypoestrogenic effects in baboons.

Interleukin-4 Stimulates Proliferation of Endometriotic Stromal Cells

“…TNF-␣ is a typical proinflammatory cytokine that plays multiple roles in the progression of endometriosis, 30,37,38 and TNF-␣-targeted suppression by specific drugs has been shown to inhibit the development of endometriosis in baboons. 39,40 The present study demonstrated the synergistic effect of IL-4 and TNF-␣ to stimulate the proliferation of ESCs. The finding is interesting in that Th2 immune response may accelerate the progress of the disease in synergy with another inflammatory mediator.…”

PPAR-gamma receptor ligand induces regression of endometrial explants in baboons: A prospective, randomized, placebo- and drug-controlled study

“…An ideal treatment would eliminate endometriotic lesions, prevent recurrence and not impede ovulation. Immune modulating drugs have been studied as candidate treatment options (4-8) including a recent successful study of recombinant human tumor necrosis factor binding protein in the baboon model of endometriosis (9)(10)(11).…”

“…Surgically transplanted endometrial tissue in the baboon provides a primate model to study the effects of experimental drugs on ectopic endometrial tissue (10,11,20). Baboon endometriotic implants show histologic transformations similar to those seen in human endometriotic lesions.…”

TNF system in eutopic endometrium from women with endometriosis

“…The appearance of sTNFR in the plasma or other fluids in several chronic inflammatory disorders may have a protective role, neutralizing TNF bioactivity to prevent its adverse pathological actions [18,33,34]. Even more, the pharmacological use of a soluble form of TNFR1 in animal model of endometriosis reduced the lesion area and induced disease regression [35,36], indicating its potential clinical use.…”