Secondary lymphoid tissue and costimulation-blockade resistant rejection: A nonhuman primate renal transplant study

Michael S. Mulvihill, Kannan P. Samy, Qimeng A. Gao, Robin Schmitz, Robert P. Davis, Brian Ezekian, Francis Leopardi, Mingqing Song, Tam How, Kyha Williams, Andrew Barbas, Bradley Collins, Allan D. Kirk

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Naïve T cell activation requires antigen presentation combined with costimulation through CD28, both of which optimally occur in secondary lymphoid tissues such as lymph nodes and the spleen. Belatacept impairs CD28 costimulation by binding its ligands, CD80 and CD86, and in doing so, impairs de novo alloimmune responses. However, in most patients belatacept is ineffective in preventing allograft rejection when used as a monotherapy, and adjuvant therapy is required for control of costimulation-blockade resistant rejection (CoBRR). In rodent models, impaired access to secondary lymphoid tissues has been demonstrated to reduce alloimmune responses to vascularized allografts. Here we show that surgical maneuvers, lymphatic ligation, and splenectomy, designed to anatomically limit access to secondary lymphoid tissues, control CoBRR and facilitate belatacept monotherapy in a nonhuman primate model of kidney transplantation without adjuvant immunotherapy. We further demonstrate that animals sustained on belatacept monotherapy progressively develop an increasingly naïve T and B cell repertoire, an effect that is accelerated by splenectomy and lost at the time of belatacept withdrawal and rejection. These pilot data inform the role of secondary lymphoid tissues on the development of CoBRR and the use of costimulation molecule–focused therapies.

Original languageEnglish
Pages (from-to)2350-2357
Number of pages8
JournalAmerican Journal of Transplantation
Issue number8
StatePublished - Aug 2019
Externally publishedYes


  • animal models: nonhuman primate
  • antigen presentation/recognition
  • basic (laboratory) research/science
  • costimulation
  • immunobiology
  • immunosuppressant - fusion proteins and monoclonal antibodies: belatacept
  • immunosuppression/immune modulation
  • kidney transplantation/nephrology
  • lymphocyte biology: differentiation/maturation
  • translational research/science


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