basic immunology of the mouse (and human) nicholas p. restifo, md october 19, 2015

Basic Immunology of the Mouse (and Human)

Nicholas P. Restifo, MD

October 19, 2015

Life started on earth about 3.5 billion years ago:mammals are a ‘recent’ development

Meet your great, great~50M-grandfather

Figure 8-1

Schematic Diagram Of The CD8 and CD4 Coreceptors

How T cell receptors, peptides and MHC molecules fit together

Schematic map of the human and mouse MHC superloci

Nomenclature of major histocompatibility complex (MHC)

Mouse

Human

Kb

Location (locus)

Strain designation

Naming MHC molecules is easy

All MHC molecules in this C57BL/6 mouse are called b

All MHC molecules in this BALB/c mouse are called d

CD8+ T cell

CD4+ T cell

Tumor cell

AntigenPresenting

Cell

TumorAntigen

What do T cells “see?”

T-cell recognition of antigens is MHC restricted

Figure 3-22

Pathways of antigen processing and presentation

TCR-peptide-MHC Crystal Structure

Figure 4-11The germline organization of the human

T-cell receptor and β loci

The numbers of human T-cell receptor gene segments and the sources of T-cell receptor diversity compared with those of immunoglobulins

Adoptive cell transfer (ACT) in mouse and man

Tumor isestablished

time

Ablate host immune system

Adoptively transfer T cells

Add vaccine and cytokine support

Tumor regression?

‘TIL’-based adoptive immunotherapy

t

t

T

Infusion of tumour-specific T cells into

patient

T Fragmentation of

tumour mass

t

Activation and selection of T cells

T cell growth factors (such as IL-2)T cell growth factors

(such as IL-2)

Add T cell growth factors (such as IL-2)

tChemotherapy+/- irradiation

Restifo, NP, et al,Nat Rev Immunol,

April, 2012

Expansion of tumour-specific T cell populations

T

Survival of patients with metastatic melanoma treated with adoptive cell transfer therapy and IL-2

93 patients treated with adoptive transfer of TIL: 9/13/2000-8/30/2009Dudley, J Clin Oncol, 2008; Rosenberg, Clin Cancer Res, 2011.

Median follow-up time 79 months (n=93)