Despite improved immunosuppression and routine PRA screening, alloreactive antibodies (alloAb) mediate a significant proportion of acute allograft rejection episodes and contribute to the development of chronic rejection. Production of pathogenic alloAb isotypes requires interactions between B cells and helper CD4 T cells specific for donor antigens. Typically, this help occurs in germinal centers within secondary lymphoid organs and is dependent on CD40/CD154 costimulatory pathway. However, the T cell repertoire of many humans contains alloreactive memory T cells that are resistant to immunosuppression or costimulatory blockade. Our preliminary data show that donor-reactive memory CD4 T cells induce higher titers of alloAb compared to naive CD4 T cells even in the absence of conventional germinal center formation and CD40/CD154 interaction. However, the mechanisms underlying the observed high alloAb titers as well as anatomical sites and molecular requirements of help by memory CD4 T cells are still unknown and need to be tested. The goal of this study is to identify functional phenotype of memory CD4 T cells providing help for alloreactive B cells and to investigate the characteristic features and requirements for this help. We have developed a mouse model of kidney transplantation to study donor-specific alloAb responses induced by memory CD4 T cells. We hypothesize that compared to naive cells, memory CD4 T cells initiate enhanced development of GCs and greater proliferation of B cells, promote production of alloAb with higher affinities for donor antigens and induce enhanced development of long-lived Ab secreting plasma cells and memory B cells. We further propose that while follicular helper memory T cells are superior in inducing alloAb responses compared to other lineages, help by memory CD4 T cells can occur outside of typical germinal centers and can bypass the requirement for CD40/CD154 interaction via alternative molecular pathways such as TLR and BAFF/APRIL signaling. We will test this hypothesis in three Specific Aims:
Aim 1. To investigate the mechanisms of superior alloantibody production induced by donor-specific memory CD4 T cells in response to renal allografts.
Aim 2. To identify functional phenotype of memory CD4 T cells capable of providing help for alloantibody production after renal allograft placement.
Aim 3. To determine the location and molecular requirements of help provided by memory CD4 T cells for alloantibody production.

Public Health Relevance

Antibody-mediated injury to transplanted organ is a significant problem in modern clinical transplantation. In conjunction with two other projects in the program, this work will provide valuable insights into the mechanisms of acute humoral rejection of renal allogtrafts. The generated information may be used to identify recipients with high risk of de novo alloAb production and to design future therapies aimed at preventing alloAb production in T cell sensitized transplant patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI087586-04
Application #
8470537
Study Section
Special Emphasis Panel (ZAI1-PTM-I)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$361,398
Indirect Cost
$131,208
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Baldwin 3rd, William M; Valujskikh, Anna; Fairchild, Robert L (2016) Mechanisms of antibody-mediated acute and chronic rejection of kidney allografts. Curr Opin Organ Transplant 21:7-14
Gorbacheva, Victoria; Fan, Ran; Fairchild, Robert L et al. (2016) Memory CD4 T Cells Induce Antibody-Mediated Rejection of Renal Allografts. J Am Soc Nephrol 27:3299-3307
Kohei, Naoki; Tanaka, Toshiaki; Tanabe, Kazunari et al. (2016) Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts. Kidney Int 89:1293-306
Iida, Shoichi; Tsuda, Hidetoshi; Tanaka, Toshiaki et al. (2016) IL-1 Receptor Signaling on Graft Parenchymal Cells Regulates Memory and De Novo Donor-Reactive CD8 T Cell Responses to Cardiac Allografts. J Immunol 196:2827-37
Baldwin 3rd, W M; Morelli, A E (2016) Strategically Altering the Balance of Macrophage Subpopulations to Inhibit Chronic Rejection. Am J Transplant 16:2510-1
Ayasoufi, Katayoun; Fan, Ran; Fairchild, Robert L et al. (2016) CD4 T Cell Help via B Cells Is Required for Lymphopenia-Induced CD8 T Cell Proliferation. J Immunol 196:3180-90
Gorbacheva, V; Ayasoufi, K; Fan, R et al. (2015) B cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) mediate CD40-independent help by memory CD4 T cells. Am J Transplant 15:346-57
Kuo, Hsiao-Hsuan; Fan, Ran; Dvorina, Nina et al. (2015) Platelets in early antibody-mediated rejection of renal transplants. J Am Soc Nephrol 26:855-63
Valujskikh, Anna N (2015) B cells regulate antidonor T-cell reactivity in transplantation. Kidney Int 88:444-6
Gorbacheva, Victoria; Fan, Ran; Wang, Xi et al. (2015) IFN-γ production by memory helper T cells is required for CD40-independent alloantibody responses. J Immunol 194:1347-56

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