Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

GVHD like skin eruption post-autologous stem cell transplantation

Bone Marrow Transplantation (2024)Cite this article

Subjects

With identical major and minor human leukocyte antigen, how did GVHD develop in patients undergoing syngeneic- or auto-HCT? Glazier et al. [4] initially demonstrated in animal transplant models that the phenomenon indistinguishable from classic acute GVHD could develop in CsA-treated and lethally irradiated rats after syngeneic or autologous BM reconstitution. These findings were later confirmed by other researchers and subsequent studies using preclinical models and human samples from CsA-induced auto GVHD. These highlight the following key points; (1) autoreactive CD8 + T cell clones that recognize MHC class II determinants in association with Class II-associated invariant chain peptide (CLIP) molecules are responsible for the development of auto-GVHD, (2) regulatory T cells (Tregs) act as a counterpart to these CD8 + T cells and prevents auto-GVHD, (3) thymus has an essential role in generating both autoreactive and immunoregulatory T cells, (4) CsA treatment (potentially other calcineurin inhibitors) hampers the central tolerance process, wherein potentially autoreactive T cells are eliminated in the thymus.

What can be said about these findings in CsA-induced auto-GVHD animal models as they pertain to spontaneous auto-GVHD cases? While instructive, it must be admitted that the mechanisms and factors driving CsA-induced auto-GVHD and spontaneous auto-GVHD remain to be completely elucidated. While thymopoiesis and central tolerance may play a fundamental role in mouse models of CsA-induced auto-GVHD, thymopoiesis does not contribute considerably to T cell reconstitution until at least 6 months post-transplant in patients [5]. Onset of auto-GVHD predominantly occurs within 2–3 weeks of transplant where thymic-independent peripheral expansion of infused T cells is likely to play the major role in immune reconstitution [6]. The origin of autoreactive CD8 + T cells against self-MHC II antigen are thus more likely to arise from break of peripheral tolerance than central tolerance. Although self-reactive T cells are deleted in the thymus through negative selection and are expected to be absent in the periphery, some can nevertheless be found in the blood. In this situation, break of peripheral tolerance leads to the expansion of autoreactive CD8 + T cells driven by self-antigens and cytokines elaborated from injured tissues, as well as innate immune activation incurred by preparative conditioning procedure. Indeed, it is likely that impairment in function and delayed reconstitution of Tregs, influenced by pre-treatment chemotherapy and host susceptibility factors is at the heart of spontaneous auto-GVHD pathology. In the context of peripheral tolerance, programmed death (PD) 1 and programmed death-ligand 1 (PD-L1) pathway may also contribute to drive autoinflammation in auto-GVHD. PD-1−/− phenotype mice develop a lupus-like glomerulonephritis and destructive arthritis, accompanied by the activation of potentially autoreactive T cells in vivo [7]. Beyond its influence on the effector T cells, PD-1 ligation increases the generation of induced T regs from naïve CD4 + T cells and enhances their suppressive function, ultimately enabling the restraint of pathogenic T cells that have escaped into the periphery [8]. In a murine allogeneic transplant model [9], while both ileum and heart had a similar repertoire of infiltrating T cells, the ileum was only susceptible to T-cell-mediated tissue destruction, whereas the heart was not. PD-L1 expression was significantly elevated in heart tissue but almost absent in the ileum. These findings suggest that the PD1-PD-L1 pathway may involve organ-specific peripheral tolerance mechanisms and play a role in either facilitating or protecting against T-cell-mediated tissue damage responsible for GVHD. Currently, a series of publications report that prior PD-1 blockade possibly alters the post-HCT course by amplifying the graft-versus-tumor effect while increasing the risk of GVHD [10]. Although most clinical reports on this topic are derived from allo-HCT settings, taken together, it is tempting to speculate that the previous exposure to anti-PD-1 treatment in our second case may have contributed to their susceptibility to developing auto-GVHD. In addition, the relatively high occurrence of auto-GVHD in the peri-engraftment period raises the possibility of a connection with engraftment syndrome. Moreover, engraftment syndrome and auto-GVHD have similar clinical manifestations and exhibit indistinguishable skin biopsy pathological findings. As Cornell et al. have suggested [11], auto-GVHD may fall on a spectrum with engraftment syndrome as an autoinflammatory consequence of breakdown in self-tolerance after auto-HCT.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Images from Hematoxylin and Eosin (H&E) histologic sections of the left upper extremity punch biopsy.

References

  1. Thein SL, Goldman JM, Galton DA. Acute ‘graft-versus-host disease’ after autografting for chronic granulocytic leukemia in transformation. Ann Intern Med. 1981;94:210–1.

    Article  CAS  PubMed  Google Scholar 

  2. Rappeport J, Mihm M, Reinherz E, Lopansri S, Parkman R. Acute graft-versus-host disease in recipients of bone-marrow transplants from identical twin donors. Lancet. 1979;2:717–20.

    Article  CAS  PubMed  Google Scholar 

  3. Otegbeye F, Gale RP, Lazarus HM. Autologous GVHD? Bone Marrow Transpl. 2014;49:1349–51.

    Article  CAS  Google Scholar 

  4. Glazier A, Tutschka PJ, Farmer ER, Santos GW. Graft-versus-host disease in cyclosporin A-treated rats after syngeneic and autologous bone marrow reconstitution. J Exp Med. 1983;158:1–8.

    Article  CAS  PubMed  Google Scholar 

  5. Janeczko-Czarnecka M, Rybka B, Ryczan-Krawczyk R, KaŁwak K, Ussowicz M. Thymic activity in immune recovery after allogeneic hematopoietic stem cell transplantation in children. Cent Eur J Immunol. 2020;45:151–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. van den Brink MRM, Velardi E, Perales M-A. Immune reconstitution following stem cell transplantation. Hematology. 2015;2015:215–9.

    Article  PubMed  Google Scholar 

  7. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141–51.

    Article  CAS  PubMed  Google Scholar 

  8. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Schilbach K, Schick J, Wehrmann M, Wollny G, Simon P, Schlegel PG, et al. PD-1-PD-L1 pathway is involved in suppressing alloreactivity of heart infiltrating t cells during murine GVHD across minor histocompatibility antigen barriers. Transplantation. 2007;84:214–22.

    Article  CAS  PubMed  Google Scholar 

  10. Merryman RW, Castagna L, Giordano L, Ho VT, Corradini P, Guidetti A, et al. Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma. Leukemia. 2021;35:2672–83.

    Article  CAS  PubMed  Google Scholar 

  11. Cornell RF, Hari P, Drobyski WR. Engraftment syndrome after autologous stem cell transplantation: an update unifying the definition and management approach. Biol Blood Marrow Transpl. 2015;21:2061–8.

    Article  Google Scholar 

  12. Holmberg L, Kikuchi K, Gooley TA, Adams KM, Hockenbery DM, Flowers MED et al. Gastrointestinal graft-versus-host disease in recipients of autologous hematopoietic stem cells: incidence, risk factors, and outcome. Biol Blood Marrow Transplant. 2006;12:226–34.

  13. Saunders MD, Shulman HM, Murakami CS, Chauncey TR, Bensinger WI, McDonald GB. Bile duct apoptosis and cholestasis resembling acute graft-versus-host disease after autologous hematopoietic cell transplantation. Am J Surg Pathol. 2000;24:1004–8.

  14. Cogbill CH, Drobyski WR, Komorowski RA. Gastrointestinal pathology of autologous graft-versus-host disease following hematopoietic stem cell transplantation: a clinicopathological study of 17 cases. Mod Pathol Off J U S Can Acad Pathol Inc. 2011;24:117–25.

  15. Lazarus HM, Sommers SR, Arfons LM, Fu P, Ataergin SA, Kaye NM et al. Spontaneous autologous graft-versushost disease in plasma cell myeloma autograft recipients: flow cytometric analysis of hematopoietic progenitor cell grafts. Biol Blood Marrow Transplant. 2011;17:970–8.

  16. Zenz T, Ritgen M, Dreger P, Kröber A, Barth TF, Schlenk R et al. Autologous graft-versus-host disease-like syndrome after an alemtuzumab-containing conditioning regimen and autologous stem cell transplantation for chronic lymphocytic leukemia. Blood 2006;108:2127–30.

  17. Baron F, Gothot A, Salmon JP, Hermanne JP, Pierard GE, Fillet G et al. Clinical course and predictive factors for cyclosporin-induced autologous graft-versus-host disease after autologous haematopoietic stem cell transplantation. Br J Haematol 2000;111:745–53.

Download references

Funding

TKK is a recipient of American Cancer Society (ACS) Clinician Scientist Development grant (CSDG-18-198-01), ACS IRG (IRG-19-139-59, IRG-22-145-62-04), Vanderbilt Ingram Cancer Center-Cancer Center Support Grant (CCSG). We also acknowledge the Translational Pathology Shared Resource supported by NCI/NIH CCSG 5P30 CA68485-19.

Author information

Author notes

  1. These authors contributed equally: Johnathan Fraebel, Silvia Park.

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Johnathan Fraebel

  2. Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Silvia Park, Rahul Shah, Salyka Sengsayadeth, Wichai Chinratanalab, Bipin Savani, Reena V. Jayani, Adetola Kassim, Bhagirathbhai R. Dholaria & Tae Kon Kim

  3. Department of Hematology, Catholic Hematology Hospital, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea

    Silvia Park

  4. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Carlos Prieto-Granada, Emily F. Mason & Tae Kon Kim

  5. Vanderbilt-Ingram Cancer Center (VICC), Nashville, TN, 37232, USA

    Salyka Sengsayadeth, Wichai Chinratanalab, Bipin Savani, Reena V. Jayani, Adetola Kassim, Bhagirathbhai R. Dholaria & Tae Kon Kim

  6. Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN, 37232, USA

    Salyka Sengsayadeth, Wichai Chinratanalab, Bipin Savani, Adetola Kassim, Bhagirathbhai R. Dholaria & Tae Kon Kim

Authors
  1. Johnathan Fraebel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvia Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rahul Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carlos Prieto-Granada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Emily F. Mason
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Salyka Sengsayadeth
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wichai Chinratanalab
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bipin Savani
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Reena V. Jayani
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Adetola Kassim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Bhagirathbhai R. Dholaria
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tae Kon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JF conceived the case and primarily wrote the manuscript. SP conceived the case and primarily wrote the manuscript. RS contributed to writing the manuscript. CPG evaluated the pathology slides and contributed to writing the manuscript. EFM evaluated the pathology slides and contributed to writing the manuscript. SS contributed to writing the manuscript. WC contributed to writing the manuscript. BS contributed to writing the manuscript. RVJ contributed to writing the manuscript. AK contributed to writing the manuscript. BRD conceived the case, reviewed the pathology slides and contributed to writing the manuscript. TKK conceived the case, reviewed the pathology slides and primarily wrote the manuscript.

Corresponding author

Correspondence to Tae Kon Kim.

Ethics declarations

Competing interests

TKK is a consultant for Agenus and Immunobiome. TKK has received a research funding from Nextcure, that is not relevant to this manuscript. The other authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fraebel, J., Park, S., Shah, R. et al. GVHD like skin eruption post-autologous stem cell transplantation. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02259-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41409-024-02259-6

Search

Advanced search

Quick links