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Orthotopic Hind Limb Transplantation in the Mouse

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Non-myeloablative mixed chimerism approaches and tolerance, a split decision.

Bin Luo¹, William F N Chan, A M James Shapiro

¹Department of Surgery, Surgical-Medical Research Institute, University of Alberta, Edmonton, Canada.

European Journal of Immunology

|March 29, 2007

Summary

New research shows that stable mixed chimerism doesn't always prevent transplant rejection, a state called split tolerance. Specific methods are needed to achieve full tolerance, overcoming tissue-specific immune responses.

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Area of Science:

Immunology
Transplantation Biology

Background:

Stable mixed chimerism is a key strategy for inducing transplant tolerance.
However, split tolerance, where donor tissues are rejected despite chimerism, remains a challenge.

Purpose of the Study:

To investigate whether new non-myeloablative mixed chimerism protocols lead to full tolerance or split tolerance.
To define the underlying mechanisms of split tolerance in these models.

Main Methods:

Generation of fully mismatched mixed chimeras using various lymphocyte-depleting antibodies, irradiation or busulfan, and sirolimus.
Assessment of tolerance using donor skin grafts and minor antigen matching.
Analysis of immune responses using CFSE killing assays.

Main Results:

Stable mixed chimerism was achieved, but donor skin grafts were rejected, indicating split tolerance.
Targeting CD40L prevented split tolerance when combined with donor bone marrow and skin grafts.
Minor antigen matching prevented T cell-mediated rejection of donor skin grafts.
Chimeras showed tolerance to donor hematopoietic cells but not tissue-specific antigens.

Conclusions:

Split tolerance, driven by tissue-restricted antigens, hinders full tolerance in many non-myeloablative mixed chimerism protocols.
A 'tolerizing' agent is necessary to overcome split tolerance.
A model for split tolerance requirements is presented.