Prospects for anti-rejection therapies based upon CD8-dependent immunoregulation

Area of Science:

• Immunology
• Transplantation Science
• Molecular Biology

Background:

• Acute allograft rejection remains a significant challenge in organ transplantation.
• Current immunotherapies primarily focus on suppressing T cell activity.
• Alloantigen-presenting cells (allo-APCs) play a crucial role in initiating T cell responses that lead to rejection.

Purpose of the Study:

• To propose a novel immunotherapy strategy targeting allo-APCs to prevent acute allograft rejection.
• To identify and define a class of molecules, termed "coinhibitors," that can convert allo-APCs from T cell activators to inhibitors.
• To investigate the potential of the CD8 molecule as a trans-coinhibitor for modulating allo-APC function.

Main Methods:

• Utilizing antisense and sense gene transfer studies to assess the effect of CD8 on allo-APCs.
• Engineering membrane-binding variants of CD8 for protein transfer.
• Analyzing the trans-coinhibitor function of CD8 beyond its known cis-coreceptor and adhesin roles.

Main Results:

• CD8 expressed on allo-APCs demonstrated a trans-coinhibitor function, inhibiting allospecific T cell responders.
• Engineered CD8 variants retained their coinhibitor function.
• Gene transfer studies confirmed CD8's role in converting allo-APCs into T cell inhibitors.

Conclusions:

• Manipulation of allo-APC cell surface phenotype, specifically through CD8 coinhibitors, offers a promising avenue for anti-rejection immunotherapy.
• Protein transfer of CD8 variants presents a potential therapeutic strategy for organ transplantation.
• This approach could lead to improved outcomes in renal and other organ transplantation by preventing acute allograft rejection.