Will new proteins incorporating new amino acids trigger an immune response?
Introduction

This question has two components. The first is the near rhetorical question whether proteins with unnatural amino acids will be considered by the immune system as ‘non-self’. Unless, by chance, the unnatural amino acid resembles some normal macromolecular component, the answer is obviously that it will be regarded as ‘non-self’.

The second question is, to my mind, much more interesting, but does not appear to be considered (or has been taken for granted) in the answer by @Astrolamb. This is whether the immune response would cause such artificial proteins to be eliminated, if  administered therapeutically. It is important, at this juncture, to emphasize that proteins containing unnatural amino acids as the result of expanding the genetic code do not, in principle, raise any problems of immune ‘rejection’ that have not already been seen in ‘unnatural’ proteins containing normal amino acids. Any immune response should therefore be regarded as being to ‘non-self protein’ and rather than to ‘non-self amino acid’.

As there have been many such studies with the latter proteins (and with proteins containing unnatural amino acids introduced by chemical modification) there are extensive studies on which to base an answer. An immunologist would be a better person to do this, but in the absence of any “immune response” I will attempt an answer from my perusal of the literature, leaning particularly on:

K. Wals and H. Ovaa “Unnatural amino acid incorporation in E. coli: current and future applications in the design of therapeutic proteins” Front. Chem 2, 1–12 (2014)

and

B. Leader  et al. “Protein therapeutics: a summary and pharmacological classification” Nature Reviews Drug Discovery 7, 21–39 (2008)

I welcome comments suggesting improvements or corrections.

Summary

The question asks: 


  “if new proteins are made from amino acids that don’t naturally occur,
  won’t the body reject them?”


which I take to mean:


  “if new proteins are made from amino acids that don’t naturally occur,
  won’t they induce an immune response which will render them
  ineffective?”


The brief answer to this is:


It depends — the immunogenicity of foreign proteins varies.
Even if an immune response is elicited this may not necessarily render such proteins ineffective.
In some cases the therapeutic intention is actually to provoke an immune response — to make a weakly immunogenic protein more so.


Foreign proteins vary in immunogenicity

The crux of the answer to this question lies in the following:


  The fact that a protein used for therapeutic purposes differs from
  those in a human subject does not in itself mean that it will invoke
  an immune response.


Let us consider two examples to illustrate this. 

The first is the case of porcine insulin, which has been administered to patients for many years, but has one amino acid different from human insulin. Regarding such non-human insulin this review states that “severe immunological complications occur rarely, and less severe events affect a small minority of patients”.

The second example is taken from more recent work by D-A. Silva et al. in designing artificial proteins. (See also Nature News &amp; Views summary). They designed mimics of the cytokines, interleukin-2 and interleukin-5, that had extensive differences in helix organization and amino acid sequence from the native proteins. However they reported that “Immunogenicity against the de novo designed proteins appears to be low”.

It turns out that  a wide variety of factors affect the immunogenicity of foreign macromolecules, so that even if a therapeutic protein elicits an immune response it may be weak enough to allow the therapeutic action to occur. In the work just cited, Silva et al. suggest that the reason for the low immunogenicity might be “the small size and high stability” of the proteins on the basis of previous work they had performed with 20,000 mini-proteins.

Admittedly, in some cases a strong immune response will occur and can obviously be a problem, so that measures need to be taken to reduce the immunogenicity. This is widely recognized and discussed in the following paper:

V. Brinks et al. “Immunogenicity of Therapeutic Proteins: The Use of Animal Models” Pharm Res (2011) 28:2379–2385 

Sometimes chemical modification of proteins can actually reduce their immunogenicity, as is the case for polyethylene glycol in relation to interferon (B. Leader et al. review, cited above).

Use of therapeutic proteins to provoke an immune response

One use envisaged for modified proteins is in cancer immunotherapy. In brief, the objective is to try to make the body mount an immune response against cancer cells, which may exhibit ‘foreign’ tumour antigens. However, in many cases these differences from normal cells are not sufficient to provoke an adequate immune response. It is has been shown that modifying retinol binding protein by introducing an unnatural amino acid can help overcome the self-tolerance to tumours in mice, suggesting a possible use in cancer immunotherapy  (J. Grünewald et al. “Mechanistic studies of the immunochemical termination of self-tolerance with unnatural amino acids” PNAS (2009) 106, 4337–4342).

Conclusion

Proteins containing unnatural amino acids as the result of expanding the genetic code do not, in principle, raise any problems of immune ‘rejection’ that have not already been seen in ‘unnatural’ proteins containing normal amino acids or chemically modified amino acids. The problem of potential immunogenicity is widely recognized and has been extensively studied by those wishing to develop the considerable therapeutic potential of all such proteins.