title: Harnessing the physiology of lymphopenia to support adoptive immunotherapy in lymphoreplete hosts.
abstract: Lymphopenia enhances the effectiveness of adoptive immunotherapy by facilitating expansion of transferred T cells but also limits the T-cell repertoire available to mediate immune responses and, in humans, is associated with chronic immune dysfunction. Previous studies concluded that lymphopenia augments adoptive immunotherapy by diminishing Tregs and increasing homeostatic cytokines. We sought to determine whether targeted therapies that replicate the physiology of lymphopenia in lymphoreplete hosts could provide a similarly supportive milieu. Pmel-1 T cells were transferred to B16-bearing lymphopenic versus lymphoreplete mice receiving alphaCD25 and/or recombinant human interleukin-7. Although CD25-based Treg depletion was inefficient because of peripheral expansion of CD4+CD25-FOXP3+ cells, outcomes were better in alphaCD25-treated lymphoreplete hosts than in lymphopenic hosts, and adoptive immunotherapy was most effective in lymphoreplete hosts receiving alphaCD25 plus recombinant human interleukin-7. Lymphopenic hosts supported increased proliferation of adoptively transferred antigen-specific T cells, but cells transferred to lymphoreplete recipients receiving targeted therapies showed superior function. Further, determinant spreading was substantial in lymphoreplete hosts but absent in lymphopenic hosts. These results demonstrate that targeted therapies delivered to mimic the "physiology of lymphopenia" enhance the efficacy of adoptive immunotherapy in lymphoreplete hosts and provide a potentially superior alternative to the induction of lymphopenia.
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Cui
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Joanna
authors.initials: J
authors.lastname: Meadors
authors.forename: Rita
authors.initials: R
authors.lastname: Poon
authors.forename: Martin
authors.initials: M
authors.lastname: Guimond
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Mackall
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology / Q000494:pharmacology; D008231:Lymphopenia / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation*
chemical_list: C508605:IL7 protein, human; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D015851:Interleukin-7
references.citation: J Immunol. 1996 Jun 15;156(12):4609-16
references.pmid: 8648103
references.citation: Blood. 2001 Mar 15;97(6):1525-33
references.pmid: 11238086
references.citation: Blood. 1997 Nov 1;90(9):3789-98
references.pmid: 9345067
references.citation: Arch Intern Med. 1994 Jul 25;154(14):1561-73
references.pmid: 7913314
references.citation: Nat Immunol. 2009 Feb;10(2):149-57
references.pmid: 19136960
references.citation: Nat Rev Immunol. 2006 Aug;6(8):595-601
references.pmid: 16868550
references.citation: J Immunother. 2006 May-Jun;29(3):313-9
references.pmid: 16699374
references.citation: Blood. 2001 May 15;97(10):2983-90
references.pmid: 11342421
references.citation: J Clin Invest. 2007 May;117(5):1204-12
references.pmid: 17476350
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19414-9
references.pmid: 19033460
references.citation: J Exp Med. 2003 Aug 18;198(4):569-80
references.pmid: 12925674
references.citation: J Immunol. 2007 Oct 1;179(7):4919-28
references.pmid: 17878392
references.citation: Semin Immunol. 2007 Oct;19(5):318-30
references.pmid: 18023361
references.citation: Semin Immunol. 2005 Jun;17(3):231-7
references.pmid: 15826828
references.citation: Immunol Res. 2008;42(1-3):182-96
references.pmid: 18949448
references.citation: Arthritis Rheum. 2008 Feb;58(2):370-5
references.pmid: 18240243
references.citation: Nature. 2006 Feb 9;439(7077):682-7
references.pmid: 16382236
references.citation: J Exp Med. 2005 Oct 3;202(7):907-12
references.pmid: 16203864
references.citation: Science. 2002 Oct 25;298(5594):850-4
references.pmid: 12242449
references.citation: J Clin Oncol. 2005 Apr 1;23(10):2346-57
references.pmid: 15800326
references.citation: Microbes Infect. 2002 Apr;4(5):531-7
references.pmid: 11959508
references.citation: Immunol Rev. 2008 Apr;222:5-8
references.pmid: 18363991
references.citation: Nat Rev Immunol. 2002 Feb;2(2):85-95
references.pmid: 11910899
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):16004-9
references.pmid: 15505208
references.citation: Cancer Res. 2002 Dec 15;62(24):7328-34
references.pmid: 12499276
references.citation: Am J Hematol. 1997 Feb;54(2):131-8
references.pmid: 9034287
references.citation: J Exp Med. 2008 Jul 7;205(7):1701-14
references.pmid: 18573906
references.citation: Nat Med. 2008 Nov;14(11):1264-70
references.pmid: 18978797
references.citation: J Transl Med. 2008 Mar 11;6:12
references.pmid: 18334033
references.citation: Immunol Today. 1997 May;18(5):245-51
references.pmid: 9153957
references.citation: Trends Immunol. 2005 Feb;26(2):111-7
references.pmid: 15668127
references.citation: J Immunol Methods. 2008 Apr 20;333(1-2):167-79
references.pmid: 18295790
references.citation: Nat Rev Cancer. 2008 Apr;8(4):299-308
references.pmid: 18354418
references.citation: J Autoimmun. 2000 Jun;14(4):275-7
references.pmid: 10882052
references.citation: J Immunother. 2008 Feb-Mar;31(2):189-98
references.pmid: 18481388
references.citation: N Engl J Med. 1995 Jan 19;332(3):143-9
references.pmid: 7800006
references.citation: J Clin Invest. 2007 Aug;117(8):2197-204
references.pmid: 17657310
references.citation: Immunity. 1999 Aug;11(2):173-81
references.pmid: 10485652
references.citation: Immunity. 1999 Aug;11(2):183-90
references.pmid: 10485653
references.citation: J Clin Invest. 2008 Jan;118(1):294-305
references.pmid: 18060041
references.citation: Immunol Rev. 1986 Jun;91:159-94
references.pmid: 3525393
references.citation: J Exp Med. 2002 Jun 17;195(12):1515-22
references.pmid: 12070279
references.citation: Immunol Rev. 2006 Aug;212:149-62
references.pmid: 16903912
references.citation: J Immunother. 2004 Sep-Oct;27(5):329-38
references.pmid: 15314541
references.citation: J Clin Invest. 2005 Apr;115(4):930-9
references.pmid: 15776111
references.citation: J Exp Med. 1998 Jul 20;188(2):277-86
references.pmid: 9670040
references.citation: J Immunol. 2005 Jun 1;174(11):6571-6
references.pmid: 15905493
references.citation: J Clin Oncol. 2008 Nov 10;26(32):5233-9
references.pmid: 18809613
references.citation: Clin Immunol. 2006 Aug;120(2):121-8
references.pmid: 16766227
references.citation: N Engl J Med. 2008 Jun 19;358(25):2698-703
references.pmid: 18565862