Sex as a biological variable: Mechanistic insights and clinical relevance in solid organ transplantation

Affiliations

¹ Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
² Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Regenerative Medicine and Experimental Surgery, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Lower Saxony, Germany.
³ Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Surgery, CVK/CCM, Charité Universitätsmedizin Berlin, Berlin, Germany.
⁴ Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan.
⁵ Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité (DHZC), Berlin, Germany.
⁶ Department of Medicine, Division of Cardiology, Columbia University Irving Medical Center, Columbia University, New York, New York, USA.
⁷ Department of Surgery, University of Chicago, Chicago, Illinois, USA.
⁸ Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: stullius@bwh.harvard.edu.

PMID: 37543092
PMCID: PMC10838351
DOI: 10.1016/j.ajt.2023.07.022

Review

Sex as a biological variable: Mechanistic insights and clinical relevance in solid organ transplantation

Yao Xiao et al. Am J Transplant. 2023 Nov.

. 2023 Nov;23(11):1661-1672.

doi: 10.1016/j.ajt.2023.07.022. Epub 2023 Aug 4.

Authors

Affiliations

¹ Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
² Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Regenerative Medicine and Experimental Surgery, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Lower Saxony, Germany.
³ Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Surgery, CVK/CCM, Charité Universitätsmedizin Berlin, Berlin, Germany.
⁴ Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan.
⁵ Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité (DHZC), Berlin, Germany.
⁶ Department of Medicine, Division of Cardiology, Columbia University Irving Medical Center, Columbia University, New York, New York, USA.
⁷ Department of Surgery, University of Chicago, Chicago, Illinois, USA.
⁸ Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: stullius@bwh.harvard.edu.

PMID: 37543092
PMCID: PMC10838351
DOI: 10.1016/j.ajt.2023.07.022

Abstract

Biological sex affects immunity broadly, with recognized effects on the incidence and severity of autoimmune diseases, infections, and malignancies. Consequences of sex on alloimmunity and outcomes in solid organ transplantation are less well defined. Clinical studies have shown that donor and recipient sex independently impact transplant outcomes, which are further modified by aging. Potential mechanisms have thus far not been detailed and may include hormonal, genetic, and epigenetic components. Here, we summarize relevant findings in immunity in addition to studies in clinical and experimental organ transplantation detailing the effects of biological sex on alloimmunity. Understanding both clinical impact and mechanisms is expected to provide critical insights on the complexity of alloimmune responses, with the potential to fine-tune treatment and allocation while providing a rationale to include both sexes in transplant research.

Keywords: aging; alloimmunity; estrogen receptor; sex hormone; solid organ transplantation.

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Conflict of interest statement

Disclosure

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Figures

**Figure 1:. Sex differences affect transplant outcomes in a multifaceted way.**
Sex has a significant impact on immunogenicity and immune response through genetic modifications on chromosomes and genes, as well as through hormone-mediated cell signaling pathways. Moreover, biological sex impacts drug metabolism, susceptibility and resistance to IRI, and environmental factors that interact and affect transplant outcomes in an age-modified manner. IRI, ischemia-reperfusion injury. Figure created using BioRender.

**Figure 2:. Estrogen levels fluctuate with age and impact innate and adaptive immunity.**
Estrogen levels increase significantly after puberty, peaking in the mid-20s followed by a slow decline that dramatically decreases with menopause. Estrogens modulate innate and adaptive immunity by regulating various immune molecules and cells including TLRs, macrophages, DCs, MDSCs, T and B cells. DC, dendritic cell; TLR, Toll-like receptor; iNOS, inducible nitric oxide synthase; pDC, plasmacytoid dendritic cell; MDSC, myeloid-derived suppressor cell; gMDSC, granulocytic myeloid-derived suppressor cell. Figure created using BioRender.

See this image and copyright information in PMC

References

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Sex as a biological variable: Mechanistic insights and clinical relevance in solid organ transplantation

Affiliations

Sex as a biological variable: Mechanistic insights and clinical relevance in solid organ transplantation

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical