PMID- 9456431
OWN - NLM
STAT- MEDLINE
DCOM- 19980226
LR  - 20080318
IS  - 1524-9557 (Print)
IS  - 1524-9557 (Linking)
VI  - 21
IP  - 1
DP  - 1998 Jan
TI  - Immunodominance across HLA polymorphism: implications for cancer immunotherapy.
PG  - 1-16
AB  - Recent advances in the understanding of the mechanisms leading to tumor 
      recognition by the immune system have shown that, at least in the case of human 
      melanoma, the majority of cytotoxic T lymphocytes (CTL) identified in association 
      with in vivo tumor regression after interleukin-2 therapy recognize nonmutated 
      molecules expressed by most melanoma cells. For this reason, peptide-based or 
      whole protein vaccination protocols against melanoma-associated antigens (MAA) 
      are ongoing in several institutions, with the goal of inducing tumor regression 
      by enhancing in vivo specific antitumor CTL reactivity. The rationale for the use 
      of such vaccines is supported by: (a) preclinical evidence that vaccination with 
      major histocompatibility complex class I restricted epitopes can enhance 
      effectively cellular immunity, (b) evidence that potent antimelanoma CTL 
      reactivity can be generated by repetitive in vitro stimulation of peripheral 
      blood monocytes with MAA, and (c) evidence that the systemic administration of 
      the same MAA can elicit antitumor CTL reactivity in vivo. As strategies are being 
      developed for the development of sound vaccines, two basic approaches are 
      investigated: one vaccination strategy is based on the administration of the 
      specific amino acid sequence recognized by the CTL in association with a 
      particular human leukocyte antigen (HLA) restriction element, and the other is 
      based on the administration of the whole antigenic molecule, which relies on the 
      organism's antigen-processing capabilities to render suitable the antigen for 
      induction of HLA class I restricted CTL reactivity in vivo. Among the various 
      factors complicating T-cell-based vaccination approaches stands the polymorphism 
      of the HLA molecules. HLA are the most polymorphic of human genes, and because 
      such polymorphism is clustered in the functional peptide-binding region, the 
      binding of antigenic peptides is necessarily restricted to specific HLA alleles. 
      This limits the interactions between CTL and antigen to specific sequences for 
      each HLA allele. For this reason, the ability of an individual antigen to 
      function as a T-cell immunogen in the context of different HLA allele restriction 
      elements is an open question. It seems logical that whole-molecule vaccines have 
      the potential advantage of broader use across patient populations. In particular, 
      large antigenic molecules may contain multiple peptide sequences with putative 
      binding properties for different HLA alleles, which in turn may elicit T-cell 
      reactivity across the polymorphism of HLA. Such a concept, however, relies on the 
      assumption that the same antigen may function with similar efficiency as an 
      immunogen in association with different HLA alleles, independently from the 
      epitopic sequence recognized in the various situations. This concept has been 
      challenged recently by several practical observations and remains, in our 
      opinion, an open question. This review will address the practical question of 
      immunogenicity of molecules across the HLA polymorphism. We postulate that the 
      complexity and success of the development of peptide-based vaccination strategies 
      depend on the severity of this restriction, which is currently only incompletely 
      studied and understood. Although no solutions are offered to the problem, 
      emphasis is placed on the importance of this question, hopefully to stimulate the 
      interest of other researchers, particularly in clinical settings, toward the 
      investigation of this type of problem.
FAU - Kim, C J
AU  - Kim CJ
AD  - Surgery Branch, National Cancer Institute, Bethesda, MD 20892, USA.
FAU - Parkinson, D R
AU  - Parkinson DR
FAU - Marincola, F
AU  - Marincola F
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - J Immunother
JT  - Journal of immunotherapy (Hagerstown, Md. : 1997)
JID - 9706083
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (HLA Antigens)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Immunodominant Epitopes)
SB  - IM
MH  - Amino Acid Sequence
MH  - Antigens, Neoplasm
MH  - HLA Antigens/*genetics/*immunology
MH  - Histocompatibility Antigens Class I/chemistry/genetics/immunology
MH  - Humans
MH  - *Immunodominant Epitopes
MH  - *Immunotherapy
MH  - Melanoma/immunology
MH  - Neoplasms/*therapy
MH  - *Polymorphism, Genetic
RF  - 129
EDAT- 1998/02/11 00:00
MHDA- 1998/02/11 00:01
CRDT- 1998/02/11 00:00
PHST- 1998/02/11 00:00 [pubmed]
PHST- 1998/02/11 00:01 [medline]
PHST- 1998/02/11 00:00 [entrez]
PST - ppublish
SO  - J Immunother. 1998 Jan;21(1):1-16.