Keratinocyte growth factor (KGF) is a recombinant form of a natural human protein that stimulates the growth of epithelial cells. KGF (generic name palifermin, trade name Kepivance) is approved by the FDA to reduce the incidence of severe mucositis (injury to the cells lining the mouth) and to shorten the time with severe mucositis in people receiving cancer chemotherapies. The AIDS Clinical Trials Group (ACTG) is currently conducting a study that will evaluate whether KGF can help restore CD4 T cell counts in individuals with a discordant response to HAART (controlled viral load but an inadequate rise in peripheral blood CD4 T cells). The rationale for the trial came from studies describing a potential role for keratinocyte growth factor in enhancing T cell production by the thymus, via the restoration of the thymic epithelium.
Now a new study just published in the online first section of the journal Blood reports encouraging data from macaques undergoing stem cell transplantation, further bolstering the rationale for studying KGF as an immune-based therapy. The study found that KGF administration increased thymic output of new naive T cells, boosting their numbers significantly compared to untreated animals.
Blood First Edition Paper, prepublished online March 20, 2007; DOI 10.1182/blood-2006-12-065623.
Submitted December 29, 2006
Accepted March 15, 2007
Ruth Seggewiss, Karin Lore, F. Javier Guenaga, Stefania Pittaluga, Joseph Mattapallil, Catherine K Chow, Richard A Koup, Kevin Camphausen, Martha C Nason, Martin Meier-Schellersheim, Robert E Donahue, Bruce R Blazar, Cynthia E Dunbar, and Daniel C Douek*
Opportunistic infections contribute to morbidity and mortality after peripheral blood progenitor cell (PBPC) transplantation and are related to a deficient T cell compartment. Accelerated T cell reconstitution may therefore be clinically beneficent. Keratinocyte growth factor (KGF) has been shown to protect thymic epithelial cells in mice. Here, we evaluated immune reconstitution after autologous CD34+ PBPC transplantation in rhesus macaques conditioned with myeloablative total body irradiation (TBI) in the absence or presence of single pre-TBI or repeated peri-transplant KGF administration. All KGF-treated animals exhibited a well-preserved thymic architecture 12 months post-graft. In contrast, thymic atrophy was observed in the majority of animals in the control group. The KGF-treated animals showed higher frequencies of naive T cells in lymph nodes post transplantation compared to the control animals. The animals given repeated doses of KGF showed the highest levels of TRECs and the lowest frequencies of Ki67+ T cells, which suggest increased thymic-dependent reconstitution in these animals. Of note, the humoral response to a T cell dependent neo-antigen was significantly higher in the KGF-treated animals compared to the control animals. Thus, our findings suggest that KGF may be a useful adjuvant therapy to augment T cell reconstitution after human PBPC transplantation.
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