Lupus-Prone Mice Resist Immune Regulation and Transplant Tolerance Induction

Area of Science:

• Immunology
• Transplantation immunology
• Autoimmune diseases

Background:

• Autoimmune diseases, such as lupus, create an immunogenic environment that hinders transplantation.
• Kidney transplant recipients with lupus face increased rejection risk, including recurrent nephritis.
• Previous studies have not fully explored transplant tolerance in highly penetrant genetic lupus models.

Purpose of the Study:

• To investigate transplant tolerance in a highly penetrant genetic model of lupus (B6.SLE123 mice).
• To identify cellular and regulatory mechanisms underlying transplant rejection in lupus.
• To establish a novel model for studying failed tolerance in autoimmunity and its clinical implications for lupus transplantation.

Main Methods:

• Utilized the fully penetrant B6.SLE123 mouse model of lupus.
• Quantified CD4 T follicular helper and germinal center B cell populations.
• Assessed the regulatory function of CD4 T regulatory cells (CD4Tregs) and CD8 T regulatory cells (CD8Tregs).
• Evaluated resistance to anti-CD45RB-mediated tolerance induction in islet allografts.

Main Results:

• B6.SLE123 mice exhibited significant expansion of CD4 T follicular helper and germinal center B cells compared to controls.
• Effector CD4 T and B cells in B6.SLE123 mice were resistant to regulation by CD4Tregs and CD8Tregs, despite normal Treg function.
• B6.SLE123 mice demonstrated resistance to tolerance induction via anti-CD45RB treatment for islet allografts, even without islet autoimmunity.

Conclusions:

• B6.SLE123 lupus-prone mice are highly resistant to transplant tolerance induction.
• This resistance is linked to immune cell expansion and impaired regulatory control.
• The B6.SLE123 model offers a new platform to dissect barriers to clinical transplantation in lupus.