Histopathological characteristics and diagnosis of rejection in human uterus transplants

Abstract

Uterus transplantation is a treatment option for women affected by absolute uterine factor infertility who wish to become pregnant and have a child. Diagnosis of rejection to guide immunosuppressive treatment is dependent on the histopathological assessment of transplant biopsies. The overall aim of this thesis was to describe the morphological characteristics of rejection in human uterus transplants and to establish a grading scheme for tissue-based diagnosis of rejection to guide treatment and facilitate comparability between studies. In paper I, we proposed a rejection grading scheme based on the histological patterns present in transplant cervical biopsies from the first Swedish clinical trial of uterus transplantation. A borderline category was introduced to account for ambiguous cases. In paper II, we analysed the explanted transplants and found that the changes in the ectocervix reflected the status of the entire organ, providing evidence that the cervix is a suitable site for tissue-based graft monitoring. We also found that borderline changes were more frequent in, but not unique to transplants. In paper III, we tested the grading scheme’s reproducibility in a multicenter study and saw moderate inter-rater and excellent intra-rater agreement. In paper IV, we assessed the expression of genes related to rejection and tissue injury in transplant biopsies. In comparison to biopsies without rejection, we saw an increasing number of differentially expressed genes from mild to severe rejections. Whilst mild rejections showed a gene expression pattern which overlapped with rejection-associated genes in other organs, moderate and severe rejections showed a mixed pattern with additional genes associated with epithelial injury. Borderline cases did not differ from non-rejection samples, providing evidence that these cases should not be regarded as rejection. In conclusion, we characterized the morphological hallmarks of rejection in human uterus transplants and proposed a robust histopathological grading scheme, which helps to guide immunosuppressive treatment.