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Homing of In Vitro-Generated Donor Antigen-Reactive CD4⁺ T Lymphocytes to Renal Allografts Is ₄₁ But Not _L2 Integrin Dependent¹

Markus H. Hammer^*,, Yuan Zhai^*, Masamichi Katori^*, Thomas Ritter, Hans-Dieter Volk, Ana J. Coito^2,* and Jerzy W. Kupiec-Weglinski^2,3,*

^* Dumont-University of California, Los Angeles Transplant Center, Department of Surgery, University of California, Los Angeles School of Medicine, Los Angeles, CA 90095; and Institute of Medical Immunology, Charité, Humboldt-University, Berlin, Germany

The extravasation and sequestration of Ag-reactive T lymphocytes into vascularized organ allografts depend on a cascade of complex interactions among circulating lymphocytes, endothelial cells, and extracellular matrix proteins. Ag-activated donor-specific CD4 T cells are major initiators and effectors in the allograft rejection response. Interfering with the intragraft homing of activated CD4 T cells may represent a novel therapeutic approach in transplant recipients. We have developed a FACS-based short-term homing assay that allows tracing in vitro-generated Ag-reactive CD4 T cells after adoptive transfer in test rat recipients. Allospecific cell lines were preincubated with anti-₄₁ or anti-_L2 mAb, because of enhanced expression of both integrin receptors after alloactivation. The pretreated Lewis_BN lymphocytes were carboxyfluorescein diacetate succinimidyl ester labeled and adoptively transferred into Lewis rat recipients of Brown Norway kidney allografts. The injection of equal numbers of PKH-26-labeled untreated cells allowed quantitative comparison of both populations in the same animal. Ex vivo treatment with anti-₄₁ mAb diminished intragraft infiltration of adoptively transferred T cells by 85% in a donor-specific fashion. In contrast, treatment with anti-_L2 mAb did not affect intragraft cell sequestration. Hence, blocking ₄₁ integrin interactions represents a novel strategy in preventing local intragraft recruitment of Ag-reactive CD4 T cells in transplant recipients.

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