Leydig cell injury as a consequence of an acute graft-versus-host reaction

Abstract

Hematopoietic stem cell transplantation (HSCT) is associated with significant posttransplantation gonadotoxicity. This deficit has been mainly attributed to pretransplantation conditioning, but lower sperm counts in humans also appear to be associated with graft-versus-host disease (GVHD) following allogeneic HSCT. However, the mechanisms leading to diminished spermatocyte levels during GVHD remain unknown. Here we demonstrate that injury to intratesticular cells occurs in unconditioned F 1 mice following the infiltration of donor alloreactive T cells during an acute graft-versus-host reaction (GVHR). Using computer-aided quantitative microscopic morphometry we demonstrate that the nadir of Leydig cell volume density coincides with the peak of intratesticular infiltration by donor T cells. Injury to Leydig cells correlates with an intratesticular inflammatory response characterized by interferon-␥ and tumor necrosis factor-␣ production. These results demonstrate impairment of testosterone-producing Leydig cells during a local alloresponse, thus representing a mechanism that contributes to gonadal insufficiency following allogeneic HSCT. IntroductionHematopoietic stem cell transplantation (HSCT) is the preferred therapy for malignant and nonmalignant disorders. 1,2 To maintain quality of life following HSCT, an appropriate reproductive status is required. A retrospective study conducted by the European Group for Blood and Marrow Transplantation (EBMT) determined, however, that the overall posttransplantation pregnancy rate is currently as low as 0.6%. 3 These results suggested that female HSC transplant recipients become transiently or permanently infertile. Likewise, most male HSC transplant recipients are reversibly or irreversibly infertile due to germ cell injury and/or Leydig cell (LC) insufficiency. [4][5][6] Posttransplantation gonadotoxicity has been attributed to the type and intensity of the pre-HSCT conditioning used. Here, myeloablative and nonmyeloablative reduced-intensity conditioning regimens can induce both spermatocyte injury and impaired LC function. 5,7,8 Gonadal dysfunction has, however, also been associated with the development of graft-versus-host disease (GVHD) because sperm counts in long-term survivors of allogeneic HSCT are much lower in GVHD patients. 9 GVHD remains a major transplantation-related toxicity that is initiated by the recognition of host alloantigens by donor-derived mature T cells, leading to injury in a restricted set of target tissues (ie, skin, liver, gastrointestinal tract). 10,11 The mechanisms leading to diminished spermatocyte levels secondary to GVHD remain unknown. Here we tested the hypothesis that injury to intratesticular cells occurs following the infiltration of alloreactive donor T cells during an acute graft-versus-host reaction (GVHR). Study designMale B6.SJL-Ptprc a Pep3 b /BoyJ mice (B6.CD45.1; H-2 b , CD45.1 ϩ ) were purchased from the Jackson Laboratories (Bar Harbor, ME) and male [C57BL/6 ϫ DBA/2]F 1 (B6D2F 1 , H-2 bd ) mice were obtained from Charl...

Children With Sickle Cell Disease: Growth and Gonadal Function After Hematopoietic Stem Cell Transplantation

“…6,27 On the other hand, in animal studies, high-dose HU is associated with germ cell apoptosis and sperm maturation abnormalities. 28,29 These changes seem to disappear after cessation of HU exposure.…”

Spermatogenesis in long-term survivors after allogeneic hematopoietic stem cell transplantation is associated with age, time interval since transplantation, and apparently absence of chronic GvHD

“…Leydig cell injury following the infiltration of donor alloreactive T cells as a manifestation of GvHD has been recently demonstrated in a mouse model. 13 In humans, lower sperm counts have been described after allogeneic HSCT associated with extensive chronic GvHD. 14 We observe here a trend to spermatogenesis production after HSCT correlated with longer intervals free of any chronic GvHD.…”

Ongoing graft-versus-host disease is a risk factor for azoospermia after allogeneic hematopoietic stem cell transplantation: a survey of the Late Effects Working Party of the European Group for Blood and Marrow Transplantation

“…This experiment did not show any evidence of a direct T-cell infiltration of seminiferous tubules, but rather speaks for an indirect effect of the GVHD on spermatogenesis, leading to a loss of Leydig cell function. 19 We cannot exclude the possibility that systemic inflammatory factors of ongoing chronic GVHD could play a role in sperm production. Nevertheless, GVHD did not affect FSH secretion.…”