Modeling immune responses to autologous and allogeneic human stem cell–derived islet grafts in vivo
Camillo Bechi Genzano, Giorgia Zanetti, Qian Du, Daniel Traum, Deeksha Lahori, Grant M. Downes, Sakshi A. Bhatele, Xiaolan Ding, Kyle D. Apley, Rebuma Firdessa Fite, Matthew Ishahak, Enrique Eduardo Sanchez-Castro, Jeffrey R. Millman, Yiming Luo, Klaus H. Kaestner, Cory Berkland, Dieter Egli, Megan Sykes, Remi J. Creusot
Camillo Bechi Genzano, Giorgia Zanetti, Qian Du, Daniel Traum, Deeksha Lahori, Grant M. Downes, Sakshi A. Bhatele, Xiaolan Ding, Kyle D. Apley, Rebuma Firdessa Fite, Matthew Ishahak, Enrique Eduardo Sanchez-Castro, Jeffrey R. Millman, Yiming Luo, Klaus H. Kaestner, Cory Berkland, Dieter Egli, Megan Sykes, Remi J. Creusot
View: Text | PDF
Research Article Endocrinology Immunology

Modeling immune responses to autologous and allogeneic human stem cell–derived islet grafts in vivo

Abstract

Stem cell–derived β cells offer a promising approach for type 1 diabetes (T1D) treatment. However, the processes of graft infiltration and rejection by immune cells remain poorly understood in humans. In this study, autologous or allogeneic stem cell–derived islets (SC-islets) were transplanted in human immune system mice and analyzed 14 to 18 weeks later. Imaging mass cytometry revealed unique characteristics of SC-islet grafts, including a high percentage of glucagon+ cells and the presence of cysts and CD57+ enterochromaffin cells, features not typically observed in endogenous or transplanted allogeneic primary pancreatic islets. Allogeneic SC-islet grafts exhibited heavy immune infiltration, cell proliferation, and pro-fibrotic processes, whereas autologous grafts showed minimal infiltration and little fibrosis. In some mice, autologous T cells expressing islet antigen-reactive (IAR) T cell receptors (TCRs) were adoptively transferred. Three weeks after transfer, autologous grafts injected with IAR-TCR+ T cells showed negligible immune infiltration, even though IAR-TCR+ T cells were detected in the spleen. Under the conditions tested, human SC-islet grafts were not rejected by an autologous immune system, even in the presence of autoreactive T cells, pointing to several limitations that remain to be addressed for a model of spontaneous autologous SC-islet infiltration and destruction.

Authors

Camillo Bechi Genzano, Giorgia Zanetti, Qian Du, Daniel Traum, Deeksha Lahori, Grant M. Downes, Sakshi A. Bhatele, Xiaolan Ding, Kyle D. Apley, Rebuma Firdessa Fite, Matthew Ishahak, Enrique Eduardo Sanchez-Castro, Jeffrey R. Millman, Yiming Luo, Klaus H. Kaestner, Cory Berkland, Dieter Egli, Megan Sykes, Remi J. Creusot

×

Figure 5

Endocrine composition of grafts.

Options: View larger image (or click on image) Download as PowerPoint
Endocrine composition of grafts. (A) Endocrine cell populations found in...
(A) Endocrine cell populations found in the grafts, represented as percentage of total endocrine cells. (B and C) Comparison of C-peptide+ (B) and C-peptide+ NKX6.1+ cells (C) among cells found in the islet region between autologous (cohort 1, cohort 2) and allogeneic grafts. (D) Representative images of endocrine cell subpopulations in autologous grafts from cohort 1. Scale bar: 100 µm. (E) Representative images of endocrine cell subpopulations and CD57 expression in the grafts of autologous cohort 2. Scale bar: 100 µm. (F) Quantification of CD57+ cells in the grafts. (G) Quantification of CD57 expression among SC-islet cell subtypes. For D and E, markers used for analysis are indicated in the figure. In autologous cohorts 1 and 2, n = 2 and n = 3 mice were injected with IAR-TCR+ T cells, respectively; n = 5 allogeneic mice were injected with additional in vitro activated polyclonal T cells (a hollow triangle represents the allogeneic mouse not injected with additional polyclonal T cells, and autologous mice injected with IAR-TCR+ T cells are represented as solid circles). Mean ± SEM; 1-way ANOVA/Tukey’s post hoc test was used for B, C, and F. *P < 0.05, **P < 0.01. C-1, cohort 1; C-2, cohort 2; SST, somatostatin.